@article {1098, title = {Genome-wide association study of blood pressure and hypertension.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Jun}, pages = {677-87}, abstract = {

Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 {\texttimes} 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 {\texttimes} 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.

}, keywords = {Blood Pressure, Cell Line, Chromosome Mapping, Chromosomes, Human, Diastole, Gene Expression Regulation, Genetic Association Studies, Genome-Wide Association Study, Humans, Hypertension, Liver, Lymphocytes, Meta-Analysis as Topic, Odds Ratio, Phenotype, Prevalence, Risk Assessment, Systole}, issn = {1546-1718}, doi = {10.1038/ng.384}, author = {Levy, Daniel and Ehret, Georg B and Rice, Kenneth and Verwoert, Germaine C and Launer, Lenore J and Dehghan, Abbas and Glazer, Nicole L and Morrison, Alanna C and Johnson, Andrew D and Aspelund, Thor and Aulchenko, Yurii and Lumley, Thomas and K{\"o}ttgen, Anna and Vasan, Ramachandran S and Rivadeneira, Fernando and Eiriksdottir, Gudny and Guo, Xiuqing and Arking, Dan E and Mitchell, Gary F and Mattace-Raso, Francesco U S and Smith, Albert V and Taylor, Kent and Scharpf, Robert B and Hwang, Shih-Jen and Sijbrands, Eric J G and Bis, Joshua and Harris, Tamara B and Ganesh, Santhi K and O{\textquoteright}Donnell, Christopher J and Hofman, Albert and Rotter, Jerome I and Coresh, Josef and Benjamin, Emelia J and Uitterlinden, Andr{\'e} G and Heiss, Gerardo and Fox, Caroline S and Witteman, Jacqueline C M and Boerwinkle, Eric and Wang, Thomas J and Gudnason, Vilmundur and Larson, Martin G and Chakravarti, Aravinda and Psaty, Bruce M and van Duijn, Cornelia M} } @article {1199, title = {Genome-wide analysis of genetic loci associated with Alzheimer disease.}, journal = {JAMA}, volume = {303}, year = {2010}, month = {2010 May 12}, pages = {1832-40}, abstract = {

CONTEXT: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD).

OBJECTIVES: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases).

DESIGN, SETTING, AND PARTICIPANTS: In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009.

MAIN OUTCOME MEASURE: Presence of Alzheimer disease.

RESULTS: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95\% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95\% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study).

CONCLUSIONS: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.

}, keywords = {Age of Onset, Aged, Alzheimer Disease, Case-Control Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Odds Ratio, Polymorphism, Single Nucleotide}, issn = {1538-3598}, doi = {10.1001/jama.2010.574}, author = {Seshadri, Sudha and Fitzpatrick, Annette L and Ikram, M Arfan and DeStefano, Anita L and Gudnason, Vilmundur and Boada, Merce and Bis, Joshua C and Smith, Albert V and Carassquillo, Minerva M and Lambert, Jean Charles and Harold, Denise and Schrijvers, Elisabeth M C and Ramirez-Lorca, Reposo and Debette, Stephanie and Longstreth, W T and Janssens, A Cecile J W and Pankratz, V Shane and Dartigues, Jean Fran{\c c}ois and Hollingworth, Paul and Aspelund, Thor and Hernandez, Isabel and Beiser, Alexa and Kuller, Lewis H and Koudstaal, Peter J and Dickson, Dennis W and Tzourio, Christophe and Abraham, Richard and Antunez, Carmen and Du, Yangchun and Rotter, Jerome I and Aulchenko, Yurii S and Harris, Tamara B and Petersen, Ronald C and Berr, Claudine and Owen, Michael J and Lopez-Arrieta, Jesus and Varadarajan, Badri N and Becker, James T and Rivadeneira, Fernando and Nalls, Michael A and Graff-Radford, Neill R and Campion, Dominique and Auerbach, Sanford and Rice, Kenneth and Hofman, Albert and Jonsson, Palmi V and Schmidt, Helena and Lathrop, Mark and Mosley, Thomas H and Au, Rhoda and Psaty, Bruce M and Uitterlinden, Andr{\'e} G and Farrer, Lindsay A and Lumley, Thomas and Ruiz, Agustin and Williams, Julie and Amouyel, Philippe and Younkin, Steve G and Wolf, Philip A and Launer, Lenore J and Lopez, Oscar L and van Duijn, Cornelia M and Breteler, Monique M B} } @article {1217, title = {Genome-wide association analysis identifies multiple loci related to resting heart rate.}, journal = {Hum Mol Genet}, volume = {19}, year = {2010}, month = {2010 Oct 01}, pages = {3885-94}, abstract = {

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 {\texttimes} 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7\% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6\%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

}, keywords = {Adult, Aged, Base Pairing, Cohort Studies, Female, Genetic Loci, Genome, Human, Genome-Wide Association Study, Heart Rate, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Rest}, issn = {1460-2083}, doi = {10.1093/hmg/ddq303}, author = {Eijgelsheim, Mark and Newton-Cheh, Christopher and Sotoodehnia, Nona and de Bakker, Paul I W and M{\"u}ller, Martina and Morrison, Alanna C and Smith, Albert V and Isaacs, Aaron and Sanna, Serena and D{\"o}rr, Marcus and Navarro, Pau and Fuchsberger, Christian and Nolte, Ilja M and de Geus, Eco J C and Estrada, Karol and Hwang, Shih-Jen and Bis, Joshua C and R{\"u}ckert, Ina-Maria and Alonso, Alvaro and Launer, Lenore J and Hottenga, Jouke Jan and Rivadeneira, Fernando and Noseworthy, Peter A and Rice, Kenneth M and Perz, Siegfried and Arking, Dan E and Spector, Tim D and Kors, Jan A and Aulchenko, Yurii S and Tarasov, Kirill V and Homuth, Georg and Wild, Sarah H and Marroni, Fabio and Gieger, Christian and Licht, Carmilla M and Prineas, Ronald J and Hofman, Albert and Rotter, Jerome I and Hicks, Andrew A and Ernst, Florian and Najjar, Samer S and Wright, Alan F and Peters, Annette and Fox, Ervin R and Oostra, Ben A and Kroemer, Heyo K and Couper, David and V{\"o}lzke, Henry and Campbell, Harry and Meitinger, Thomas and Uda, Manuela and Witteman, Jacqueline C M and Psaty, Bruce M and Wichmann, H-Erich and Harris, Tamara B and K{\"a}{\"a}b, Stefan and Siscovick, David S and Jamshidi, Yalda and Uitterlinden, Andr{\'e} G and Folsom, Aaron R and Larson, Martin G and Wilson, James F and Penninx, Brenda W and Snieder, Harold and Pramstaller, Peter P and van Duijn, Cornelia M and Lakatta, Edward G and Felix, Stephan B and Gudnason, Vilmundur and Pfeufer, Arne and Heckbert, Susan R and Stricker, Bruno H Ch and Boerwinkle, Eric and O{\textquoteright}Donnell, Christopher J} } @article {1156, title = {Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.}, journal = {Stroke}, volume = {41}, year = {2010}, month = {2010 Feb}, pages = {210-7}, abstract = {

BACKGROUND AND PURPOSE: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4\% of whom had >or=1 MRI infarct).

RESULTS: The most significant association was found with rs2208454 (minor allele frequency, 20\%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95\% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.

CONCLUSIONS: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.

}, keywords = {African Americans, Aged, Brain, Brain Infarction, Cohort Studies, DNA Mutational Analysis, Female, Gene Frequency, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Magnetic Resonance Imaging, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.109.569194}, author = {Debette, Stephanie and Bis, Joshua C and Fornage, Myriam and Schmidt, Helena and Ikram, M Arfan and Sigurdsson, Sigurdur and Heiss, Gerardo and Struchalin, Maksim and Smith, Albert V and van der Lugt, Aad and DeCarli, Charles and Lumley, Thomas and Knopman, David S and Enzinger, Christian and Eiriksdottir, Gudny and Koudstaal, Peter J and DeStefano, Anita L and Psaty, Bruce M and Dufouil, Carole and Catellier, Diane J and Fazekas, Franz and Aspelund, Thor and Aulchenko, Yurii S and Beiser, Alexa and Rotter, Jerome I and Tzourio, Christophe and Shibata, Dean K and Tscherner, Maria and Harris, Tamara B and Rivadeneira, Fernando and Atwood, Larry D and Rice, Kenneth and Gottesman, Rebecca F and van Buchem, Mark A and Uitterlinden, Andr{\'e} G and Kelly-Hayes, Margaret and Cushman, Mary and Zhu, Yicheng and Boerwinkle, Eric and Gudnason, Vilmundur and Hofman, Albert and Romero, Jose R and Lopez, Oscar and van Duijn, Cornelia M and Au, Rhoda and Heckbert, Susan R and Wolf, Philip A and Mosley, Thomas H and Seshadri, Sudha and Breteler, Monique M B and Schmidt, Reinhold and Launer, Lenore J and Longstreth, W T} } @article {1223, title = {Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels.}, journal = {PLoS Genet}, volume = {6}, year = {2010}, month = {2010 Aug 05}, abstract = {

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using approximately 2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5 x 10(-8)) or suggestive associations (p<4 x 10(-7)) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4 x 10(-7). Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.

}, keywords = {Adult, Aged, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Magnesium, Male, Middle Aged, Polymorphism, Single Nucleotide, Potassium, Sodium}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1001045}, author = {Meyer, Tamra E and Verwoert, Germaine C and Hwang, Shih-Jen and Glazer, Nicole L and Smith, Albert V and van Rooij, Frank J A and Ehret, Georg B and Boerwinkle, Eric and Felix, Janine F and Leak, Tennille S and Harris, Tamara B and Yang, Qiong and Dehghan, Abbas and Aspelund, Thor and Katz, Ronit and Homuth, Georg and Kocher, Thomas and Rettig, Rainer and Ried, Janina S and Gieger, Christian and Prucha, Hanna and Pfeufer, Arne and Meitinger, Thomas and Coresh, Josef and Hofman, Albert and Sarnak, Mark J and Chen, Yii-Der Ida and Uitterlinden, Andr{\'e} G and Chakravarti, Aravinda and Psaty, Bruce M and van Duijn, Cornelia M and Kao, W H Linda and Witteman, Jacqueline C M and Gudnason, Vilmundur and Siscovick, David S and Fox, Caroline S and K{\"o}ttgen, Anna} } @article {1325, title = {Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.}, journal = {Nature}, volume = {478}, year = {2011}, month = {2011 Sep 11}, pages = {103-9}, abstract = {

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>=140 mm Hg systolic blood pressure or >=90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

}, keywords = {Africa, Asia, Blood Pressure, Cardiovascular Diseases, Coronary Artery Disease, Europe, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypertension, Kidney Diseases, Polymorphism, Single Nucleotide, Stroke}, issn = {1476-4687}, doi = {10.1038/nature10405}, author = {Ehret, Georg B and Munroe, Patricia B and Rice, Kenneth M and Bochud, Murielle and Johnson, Andrew D and Chasman, Daniel I and Smith, Albert V and Tobin, Martin D and Verwoert, Germaine C and Hwang, Shih-Jen and Pihur, Vasyl and Vollenweider, Peter and O{\textquoteright}Reilly, Paul F and Amin, Najaf and Bragg-Gresham, Jennifer L and Teumer, Alexander and Glazer, Nicole L and Launer, Lenore and Zhao, Jing Hua and Aulchenko, Yurii and Heath, Simon and S{\~o}ber, Siim and Parsa, Afshin and Luan, Jian{\textquoteright}an and Arora, Pankaj and Dehghan, Abbas and Zhang, Feng and Lucas, Gavin and Hicks, Andrew A and Jackson, Anne U and Peden, John F and Tanaka, Toshiko and Wild, Sarah H and Rudan, Igor and Igl, Wilmar and Milaneschi, Yuri and Parker, Alex N and Fava, Cristiano and Chambers, John C and Fox, Ervin R and Kumari, Meena and Go, Min Jin and van der Harst, Pim and Kao, Wen Hong Linda and Sj{\"o}gren, Marketa and Vinay, D G and Alexander, Myriam and Tabara, Yasuharu and Shaw-Hawkins, Sue and Whincup, Peter H and Liu, Yongmei and Shi, Gang and Kuusisto, Johanna and Tayo, Bamidele and Seielstad, Mark and Sim, Xueling and Nguyen, Khanh-Dung Hoang and Lehtim{\"a}ki, Terho and Matullo, Giuseppe and Wu, Ying and Gaunt, Tom R and Onland-Moret, N Charlotte and Cooper, Matthew N and Platou, Carl G P and Org, Elin and Hardy, Rebecca and Dahgam, Santosh and Palmen, Jutta and Vitart, Veronique and Braund, Peter S and Kuznetsova, Tatiana and Uiterwaal, Cuno S P M and Adeyemo, Adebowale and Palmas, Walter and Campbell, Harry and Ludwig, Barbara and Tomaszewski, Maciej and Tzoulaki, Ioanna and Palmer, Nicholette D and Aspelund, Thor and Garcia, Melissa and Chang, Yen-Pei C and O{\textquoteright}Connell, Jeffrey R and Steinle, Nanette I and Grobbee, Diederick E and Arking, Dan E and Kardia, Sharon L and Morrison, Alanna C and Hernandez, Dena and Najjar, Samer and McArdle, Wendy L and Hadley, David and Brown, Morris J and Connell, John M and Hingorani, Aroon D and Day, Ian N M and Lawlor, Debbie A and Beilby, John P and Lawrence, Robert W and Clarke, Robert and Hopewell, Jemma C and Ongen, Halit and Dreisbach, Albert W and Li, Yali and Young, J Hunter and Bis, Joshua C and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Adair, Linda S and Lee, Nanette R and Chen, Ming-Huei and Olden, Matthias and Pattaro, Cristian and Bolton, Judith A Hoffman and K{\"o}ttgen, Anna and Bergmann, Sven and Mooser, Vincent and Chaturvedi, Nish and Frayling, Timothy M and Islam, Muhammad and Jafar, Tazeen H and Erdmann, Jeanette and Kulkarni, Smita R and Bornstein, Stefan R and Gr{\"a}ssler, J{\"u}rgen and Groop, Leif and Voight, Benjamin F and Kettunen, Johannes and Howard, Philip and Taylor, Andrew and Guarrera, Simonetta and Ricceri, Fulvio and Emilsson, Valur and Plump, Andrew and Barroso, In{\^e}s and Khaw, Kay-Tee and Weder, Alan B and Hunt, Steven C and Sun, Yan V and Bergman, Richard N and Collins, Francis S and Bonnycastle, Lori L and Scott, Laura J and Stringham, Heather M and Peltonen, Leena and Perola, Markus and Vartiainen, Erkki and Brand, Stefan-Martin and Staessen, Jan A and Wang, Thomas J and Burton, Paul R and Soler Artigas, Maria and Dong, Yanbin and Snieder, Harold and Wang, Xiaoling and Zhu, Haidong and Lohman, Kurt K and Rudock, Megan E and Heckbert, Susan R and Smith, Nicholas L and Wiggins, Kerri L and Doumatey, Ayo and Shriner, Daniel and Veldre, Gudrun and Viigimaa, Margus and Kinra, Sanjay and Prabhakaran, Dorairaj and Tripathy, Vikal and Langefeld, Carl D and Rosengren, Annika and Thelle, Dag S and Corsi, Anna Maria and Singleton, Andrew and Forrester, Terrence and Hilton, Gina and McKenzie, Colin A and Salako, Tunde and Iwai, Naoharu and Kita, Yoshikuni and Ogihara, Toshio and Ohkubo, Takayoshi and Okamura, Tomonori and Ueshima, Hirotsugu and Umemura, Satoshi and Eyheramendy, Susana and Meitinger, Thomas and Wichmann, H-Erich and Cho, Yoon Shin and Kim, Hyung-Lae and Lee, Jong-Young and Scott, James and Sehmi, Joban S and Zhang, Weihua and Hedblad, Bo and Nilsson, Peter and Smith, George Davey and Wong, Andrew and Narisu, Narisu and Stan{\v c}{\'a}kov{\'a}, Alena and Raffel, Leslie J and Yao, Jie and Kathiresan, Sekar and O{\textquoteright}Donnell, Christopher J and Schwartz, Stephen M and Ikram, M Arfan and Longstreth, W T and Mosley, Thomas H and Seshadri, Sudha and Shrine, Nick R G and Wain, Louise V and Morken, Mario A and Swift, Amy J and Laitinen, Jaana and Prokopenko, Inga and Zitting, Paavo and Cooper, Jackie A and Humphries, Steve E and Danesh, John and Rasheed, Asif and Goel, Anuj and Hamsten, Anders and Watkins, Hugh and Bakker, Stephan J L and van Gilst, Wiek H and Janipalli, Charles S and Mani, K Radha and Yajnik, Chittaranjan S and Hofman, Albert and Mattace-Raso, Francesco U S and Oostra, Ben A and Demirkan, Ayse and Isaacs, Aaron and Rivadeneira, Fernando and Lakatta, Edward G and Orr{\`u}, Marco and Scuteri, Angelo and Ala-Korpela, Mika and Kangas, Antti J and Lyytik{\"a}inen, Leo-Pekka and Soininen, Pasi and Tukiainen, Taru and W{\"u}rtz, Peter and Ong, Rick Twee-Hee and D{\"o}rr, Marcus and Kroemer, Heyo K and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Galan, Pilar and Hercberg, Serge and Lathrop, Mark and Zelenika, Diana and Deloukas, Panos and Mangino, Massimo and Spector, Tim D and Zhai, Guangju and Meschia, James F and Nalls, Michael A and Sharma, Pankaj and Terzic, Janos and Kumar, M V Kranthi and Denniff, Matthew and Zukowska-Szczechowska, Ewa and Wagenknecht, Lynne E and Fowkes, F Gerald R and Charchar, Fadi J and Schwarz, Peter E H and Hayward, Caroline and Guo, Xiuqing and Rotimi, Charles and Bots, Michiel L and Brand, Eva and Samani, Nilesh J and Polasek, Ozren and Talmud, Philippa J and Nyberg, Fredrik and Kuh, Diana and Laan, Maris and Hveem, Kristian and Palmer, Lyle J and van der Schouw, Yvonne T and Casas, Juan P and Mohlke, Karen L and Vineis, Paolo and Raitakari, Olli and Ganesh, Santhi K and Wong, Tien Y and Tai, E Shyong and Cooper, Richard S and Laakso, Markku and Rao, Dabeeru C and Harris, Tamara B and Morris, Richard W and Dominiczak, Anna F and Kivimaki, Mika and Marmot, Michael G and Miki, Tetsuro and Saleheen, Danish and Chandak, Giriraj R and Coresh, Josef and Navis, Gerjan and Salomaa, Veikko and Han, Bok-Ghee and Zhu, Xiaofeng and Kooner, Jaspal S and Melander, Olle and Ridker, Paul M and Bandinelli, Stefania and Gyllensten, Ulf B and Wright, Alan F and Wilson, James F and Ferrucci, Luigi and Farrall, Martin and Tuomilehto, Jaakko and Pramstaller, Peter P and Elosua, Roberto and Soranzo, Nicole and Sijbrands, Eric J G and Altshuler, David and Loos, Ruth J F and Shuldiner, Alan R and Gieger, Christian and Meneton, Pierre and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Gudnason, Vilmundur and Rotter, Jerome I and Rettig, Rainer and Uda, Manuela and Strachan, David P and Witteman, Jacqueline C M and Hartikainen, Anna-Liisa and Beckmann, Jacques S and Boerwinkle, Eric and Vasan, Ramachandran S and Boehnke, Michael and Larson, Martin G and Jarvelin, Marjo-Riitta and Psaty, Bruce M and Abecasis, Goncalo R and Chakravarti, Aravinda and Elliott, Paul and van Duijn, Cornelia M and Newton-Cheh, Christopher and Levy, Daniel and Caulfield, Mark J and Johnson, Toby} } @article {1298, title = {Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.}, journal = {Ann Neurol}, volume = {69}, year = {2011}, month = {2011 Jun}, pages = {928-39}, abstract = {

OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.

METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.

RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 {\texttimes} 10(-9) ; p(replication) = 1.3 {\texttimes} 10(-7) ; p(combined) = 4.0 {\texttimes} 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 {\texttimes} 10(-9) ), rs11869977 (p = 5.7 {\texttimes} 10(-9) ), rs936393 (p = 6.8 {\texttimes} 10(-9) ), rs3744017 (p = 7.3 {\texttimes} 10(-9) ), and rs1055129 (p = 4.1 {\texttimes} 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8\% of the overall mean WMH burden in the sample).

INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

}, keywords = {Aged, Aged, 80 and over, Cerebral Cortex, Chromosomes, Human, Pair 17, Cognition Disorders, Cohort Studies, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Middle Aged, Movement Disorders, Nerve Fibers, Myelinated, Polymorphism, Single Nucleotide, Residence Characteristics, RNA, Messenger}, issn = {1531-8249}, doi = {10.1002/ana.22403}, author = {Fornage, Myriam and Debette, Stephanie and Bis, Joshua C and Schmidt, Helena and Ikram, M Arfan and Dufouil, Carole and Sigurdsson, Sigurdur and Lumley, Thomas and DeStefano, Anita L and Fazekas, Franz and Vrooman, Henri A and Shibata, Dean K and Maillard, Pauline and Zijdenbos, Alex and Smith, Albert V and Gudnason, Haukur and de Boer, Renske and Cushman, Mary and Mazoyer, Bernard and Heiss, Gerardo and Vernooij, Meike W and Enzinger, Christian and Glazer, Nicole L and Beiser, Alexa and Knopman, David S and Cavalieri, Margherita and Niessen, Wiro J and Harris, Tamara B and Petrovic, Katja and Lopez, Oscar L and Au, Rhoda and Lambert, Jean-Charles and Hofman, Albert and Gottesman, Rebecca F and Garcia, Melissa and Heckbert, Susan R and Atwood, Larry D and Catellier, Diane J and Uitterlinden, Andr{\'e} G and Yang, Qiong and Smith, Nicholas L and Aspelund, Thor and Romero, Jose R and Rice, Kenneth and Taylor, Kent D and Nalls, Michael A and Rotter, Jerome I and Sharrett, Richey and van Duijn, Cornelia M and Amouyel, Philippe and Wolf, Philip A and Gudnason, Vilmundur and van der Lugt, Aad and Boerwinkle, Eric and Psaty, Bruce M and Seshadri, Sudha and Tzourio, Christophe and Breteler, Monique M B and Mosley, Thomas H and Schmidt, Reinhold and Longstreth, W T and DeCarli, Charles and Launer, Lenore J} } @article {1324, title = {Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Sep 11}, pages = {1005-11}, abstract = {

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 {\texttimes} 10(-8) to P = 2.3 {\texttimes} 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

}, keywords = {Arteries, Blood Pressure, Case-Control Studies, Follow-Up Studies, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Linkage Disequilibrium, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.922}, author = {Wain, Louise V and Verwoert, Germaine C and O{\textquoteright}Reilly, Paul F and Shi, Gang and Johnson, Toby and Johnson, Andrew D and Bochud, Murielle and Rice, Kenneth M and Henneman, Peter and Smith, Albert V and Ehret, Georg B and Amin, Najaf and Larson, Martin G and Mooser, Vincent and Hadley, David and D{\"o}rr, Marcus and Bis, Joshua C and Aspelund, Thor and Esko, T{\~o}nu and Janssens, A Cecile J W and Zhao, Jing Hua and Heath, Simon and Laan, Maris and Fu, Jingyuan and Pistis, Giorgio and Luan, Jian{\textquoteright}an and Arora, Pankaj and Lucas, Gavin and Pirastu, Nicola and Pichler, Irene and Jackson, Anne U and Webster, Rebecca J and Zhang, Feng and Peden, John F and Schmidt, Helena and Tanaka, Toshiko and Campbell, Harry and Igl, Wilmar and Milaneschi, Yuri and Hottenga, Jouke-Jan and Vitart, Veronique and Chasman, Daniel I and Trompet, Stella and Bragg-Gresham, Jennifer L and Alizadeh, Behrooz Z and Chambers, John C and Guo, Xiuqing and Lehtim{\"a}ki, Terho and Kuhnel, Brigitte and Lopez, Lorna M and Polasek, Ozren and Boban, Mladen and Nelson, Christopher P and Morrison, Alanna C and Pihur, Vasyl and Ganesh, Santhi K and Hofman, Albert and Kundu, Suman and Mattace-Raso, Francesco U S and Rivadeneira, Fernando and Sijbrands, Eric J G and Uitterlinden, Andr{\'e} G and Hwang, Shih-Jen and Vasan, Ramachandran S and Wang, Thomas J and Bergmann, Sven and Vollenweider, Peter and Waeber, G{\'e}rard and Laitinen, Jaana and Pouta, Anneli and Zitting, Paavo and McArdle, Wendy L and Kroemer, Heyo K and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Glazer, Nicole L and Taylor, Kent D and Harris, Tamara B and Alavere, Helene and Haller, Toomas and Keis, Aime and Tammesoo, Mari-Liis and Aulchenko, Yurii and Barroso, In{\^e}s and Khaw, Kay-Tee and Galan, Pilar and Hercberg, Serge and Lathrop, Mark and Eyheramendy, Susana and Org, Elin and S{\~o}ber, Siim and Lu, Xiaowen and Nolte, Ilja M and Penninx, Brenda W and Corre, Tanguy and Masciullo, Corrado and Sala, Cinzia and Groop, Leif and Voight, Benjamin F and Melander, Olle and O{\textquoteright}Donnell, Christopher J and Salomaa, Veikko and d{\textquoteright}Adamo, Adamo Pio and Fabretto, Antonella and Faletra, Flavio and Ulivi, Sheila and Del Greco, Fabiola M and Facheris, Maurizio and Collins, Francis S and Bergman, Richard N and Beilby, John P and Hung, Joseph and Musk, A William and Mangino, Massimo and Shin, So-Youn and Soranzo, Nicole and Watkins, Hugh and Goel, Anuj and Hamsten, Anders and Gider, Pierre and Loitfelder, Marisa and Zeginigg, Marion and Hernandez, Dena and Najjar, Samer S and Navarro, Pau and Wild, Sarah H and Corsi, Anna Maria and Singleton, Andrew and de Geus, Eco J C and Willemsen, Gonneke and Parker, Alex N and Rose, Lynda M and Buckley, Brendan and Stott, David and Orr{\`u}, Marco and Uda, Manuela and van der Klauw, Melanie M and Zhang, Weihua and Li, Xinzhong and Scott, James and Chen, Yii-Der Ida and Burke, Gregory L and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and D{\"o}ring, Angela and Meitinger, Thomas and Davies, Gail and Starr, John M and Emilsson, Valur and Plump, Andrew and Lindeman, Jan H and Hoen, Peter A C {\textquoteright}t and K{\"o}nig, Inke R and Felix, Janine F and Clarke, Robert and Hopewell, Jemma C and Ongen, Halit and Breteler, Monique and Debette, Stephanie and DeStefano, Anita L and Fornage, Myriam and Mitchell, Gary F and Smith, Nicholas L and Holm, Hilma and Stefansson, Kari and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Samani, Nilesh J and Preuss, Michael and Rudan, Igor and Hayward, Caroline and Deary, Ian J and Wichmann, H-Erich and Raitakari, Olli T and Palmas, Walter and Kooner, Jaspal S and Stolk, Ronald P and Jukema, J Wouter and Wright, Alan F and Boomsma, Dorret I and Bandinelli, Stefania and Gyllensten, Ulf B and Wilson, James F and Ferrucci, Luigi and Schmidt, Reinhold and Farrall, Martin and Spector, Tim D and Palmer, Lyle J and Tuomilehto, Jaakko and Pfeufer, Arne and Gasparini, Paolo and Siscovick, David and Altshuler, David and Loos, Ruth J F and Toniolo, Daniela and Snieder, Harold and Gieger, Christian and Meneton, Pierre and Wareham, Nicholas J and Oostra, Ben A and Metspalu, Andres and Launer, Lenore and Rettig, Rainer and Strachan, David P and Beckmann, Jacques S and Witteman, Jacqueline C M and Erdmann, Jeanette and van Dijk, Ko Willems and Boerwinkle, Eric and Boehnke, Michael and Ridker, Paul M and Jarvelin, Marjo-Riitta and Chakravarti, Aravinda and Abecasis, Goncalo R and Gudnason, Vilmundur and Newton-Cheh, Christopher and Levy, Daniel and Munroe, Patricia B and Psaty, Bruce M and Caulfield, Mark J and Rao, Dabeeru C and Tobin, Martin D and Elliott, Paul and van Duijn, Cornelia M} } @article {1307, title = {A genome-wide association study of aging.}, journal = {Neurobiol Aging}, volume = {32}, year = {2011}, month = {2011 Nov}, pages = {2109.e15-28}, abstract = {

Human longevity and healthy aging show moderate heritability (20\%-50\%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 {\texttimes} 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer{\textquoteright}s disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.

}, keywords = {Aging, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Longevity}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2011.05.026}, author = {Walter, Stefan and Atzmon, Gil and Demerath, Ellen W and Garcia, Melissa E and Kaplan, Robert C and Kumari, Meena and Lunetta, Kathryn L and Milaneschi, Yuri and Tanaka, Toshiko and Tranah, Gregory J and V{\"o}lker, Uwe and Yu, Lei and Arnold, Alice and Benjamin, Emelia J and Biffar, Reiner and Buchman, Aron S and Boerwinkle, Eric and Couper, David and De Jager, Philip L and Evans, Denis A and Harris, Tamara B and Hoffmann, Wolfgang and Hofman, Albert and Karasik, David and Kiel, Douglas P and Kocher, Thomas and Kuningas, Maris and Launer, Lenore J and Lohman, Kurt K and Lutsey, Pamela L and Mackenbach, Johan and Marciante, Kristin and Psaty, Bruce M and Reiman, Eric M and Rotter, Jerome I and Seshadri, Sudha and Shardell, Michelle D and Smith, Albert V and van Duijn, Cornelia and Walston, Jeremy and Zillikens, M Carola and Bandinelli, Stefania and Baumeister, Sebastian E and Bennett, David A and Ferrucci, Luigi and Gudnason, Vilmundur and Kivimaki, Mika and Liu, Yongmei and Murabito, Joanne M and Newman, Anne B and Tiemeier, Henning and Franceschini, Nora} } @article {1377, title = {Genome-wide association and functional follow-up reveals new loci for kidney function.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002584}, abstract = {

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

}, keywords = {African Americans, Aged, Animals, Caspase 9, Cyclin-Dependent Kinases, DEAD-box RNA Helicases, DNA Helicases, European Continental Ancestry Group, Female, Follow-Up Studies, Gene Knockdown Techniques, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Male, Middle Aged, Phosphoric Diester Hydrolases, Zebrafish}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002584}, author = {Pattaro, Cristian and K{\"o}ttgen, Anna and Teumer, Alexander and Garnaas, Maija and B{\"o}ger, Carsten A and Fuchsberger, Christian and Olden, Matthias and Chen, Ming-Huei and Tin, Adrienne and Taliun, Daniel and Li, Man and Gao, Xiaoyi and Gorski, Mathias and Yang, Qiong and Hundertmark, Claudia and Foster, Meredith C and O{\textquoteright}Seaghdha, Conall M and Glazer, Nicole and Isaacs, Aaron and Liu, Ching-Ti and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Struchalin, Maksim and Tanaka, Toshiko and Li, Guo and Johnson, Andrew D and Gierman, Hinco J and Feitosa, Mary and Hwang, Shih-Jen and Atkinson, Elizabeth J and Lohman, Kurt and Cornelis, Marilyn C and Johansson, Asa and T{\"o}njes, Anke and Dehghan, Abbas and Chouraki, Vincent and Holliday, Elizabeth G and Sorice, Rossella and Kutalik, Zolt{\'a}n and Lehtim{\"a}ki, Terho and Esko, T{\~o}nu and Deshmukh, Harshal and Ulivi, Sheila and Chu, Audrey Y and Murgia, Federico and Trompet, Stella and Imboden, Medea and Kollerits, Barbara and Pistis, Giorgio and Harris, Tamara B and Launer, Lenore J and Aspelund, Thor and Eiriksdottir, Gudny and Mitchell, Braxton D and Boerwinkle, Eric and Schmidt, Helena and Cavalieri, Margherita and Rao, Madhumathi and Hu, Frank B and Demirkan, Ayse and Oostra, Ben A and de Andrade, Mariza and Turner, Stephen T and Ding, Jingzhong and Andrews, Jeanette S and Freedman, Barry I and Koenig, Wolfgang and Illig, Thomas and D{\"o}ring, Angela and Wichmann, H-Erich and Kolcic, Ivana and Zemunik, Tatijana and Boban, Mladen and Minelli, Cosetta and Wheeler, Heather E and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and N{\"o}thlings, Ute and Jacobs, Gunnar and Biffar, Reiner and Endlich, Karlhans and Ernst, Florian and Homuth, Georg and Kroemer, Heyo K and Nauck, Matthias and Stracke, Sylvia and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Kovacs, Peter and Stumvoll, Michael and M{\"a}gi, Reedik and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Aulchenko, Yurii S and Polasek, Ozren and Hastie, Nick and Vitart, Veronique and Helmer, Catherine and Wang, Jie Jin and Ruggiero, Daniela and Bergmann, Sven and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Nikopensius, Tiit and Province, Michael and Ketkar, Shamika and Colhoun, Helen and Doney, Alex and Robino, Antonietta and Giulianini, Franco and Kr{\"a}mer, Bernhard K and Portas, Laura and Ford, Ian and Buckley, Brendan M and Adam, Martin and Thun, Gian-Andri and Paulweber, Bernhard and Haun, Margot and Sala, Cinzia and Metzger, Marie and Mitchell, Paul and Ciullo, Marina and Kim, Stuart K and Vollenweider, Peter and Raitakari, Olli and Metspalu, Andres and Palmer, Colin and Gasparini, Paolo and Pirastu, Mario and Jukema, J Wouter and Probst-Hensch, Nicole M and Kronenberg, Florian and Toniolo, Daniela and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and Siscovick, David S and van Duijn, Cornelia M and Borecki, Ingrid and Kardia, Sharon L R and Liu, Yongmei and Curhan, Gary C and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Franke, Andre and Pramstaller, Peter P and Rettig, Rainer and Prokopenko, Inga and Witteman, Jacqueline C M and Hayward, Caroline and Ridker, Paul and Parsa, Afshin and Bochud, Murielle and Heid, Iris M and Goessling, Wolfram and Chasman, Daniel I and Kao, W H Linda and Fox, Caroline S} } @article {6088, title = {Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1003098}, abstract = {

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00{\texttimes}10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35{\texttimes}10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28{\texttimes}10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

}, keywords = {Forced Expiratory Volume, Gene Expression, Genome, Human, Genome-Wide Association Study, HLA-DQ Antigens, HLA-DQ beta-Chains, Humans, Lung, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Potassium Channels, Inwardly Rectifying, Pulmonary Disease, Chronic Obstructive, Receptors, Cell Surface, Smoking, SOX9 Transcription Factor, Vital Capacity}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003098}, author = {Hancock, Dana B and Soler Artigas, Maria and Gharib, Sina A and Henry, Amanda and Manichaikul, Ani and Ramasamy, Adaikalavan and Loth, Daan W and Imboden, Medea and Koch, Beate and McArdle, Wendy L and Smith, Albert V and Smolonska, Joanna and Sood, Akshay and Tang, Wenbo and Wilk, Jemma B and Zhai, Guangju and Zhao, Jing Hua and Aschard, Hugues and Burkart, Kristin M and Curjuric, Ivan and Eijgelsheim, Mark and Elliott, Paul and Gu, Xiangjun and Harris, Tamara B and Janson, Christer and Homuth, Georg and Hysi, Pirro G and Liu, Jason Z and Loehr, Laura R and Lohman, Kurt and Loos, Ruth J F and Manning, Alisa K and Marciante, Kristin D and Obeidat, Ma{\textquoteright}en and Postma, Dirkje S and Aldrich, Melinda C and Brusselle, Guy G and Chen, Ting-Hsu and Eiriksdottir, Gudny and Franceschini, Nora and Heinrich, Joachim and Rotter, Jerome I and Wijmenga, Cisca and Williams, O Dale and Bentley, Amy R and Hofman, Albert and Laurie, Cathy C and Lumley, Thomas and Morrison, Alanna C and Joubert, Bonnie R and Rivadeneira, Fernando and Couper, David J and Kritchevsky, Stephen B and Liu, Yongmei and Wjst, Matthias and Wain, Louise V and Vonk, Judith M and Uitterlinden, Andr{\'e} G and Rochat, Thierry and Rich, Stephen S and Psaty, Bruce M and O{\textquoteright}Connor, George T and North, Kari E and Mirel, Daniel B and Meibohm, Bernd and Launer, Lenore J and Khaw, Kay-Tee and Hartikainen, Anna-Liisa and Hammond, Christopher J and Gl{\"a}ser, Sven and Marchini, Jonathan and Kraft, Peter and Wareham, Nicholas J and V{\"o}lzke, Henry and Stricker, Bruno H C and Spector, Timothy D and Probst-Hensch, Nicole M and Jarvis, Deborah and Jarvelin, Marjo-Riitta and Heckbert, Susan R and Gudnason, Vilmundur and Boezen, H Marike and Barr, R Graham and Cassano, Patricia A and Strachan, David P and Fornage, Myriam and Hall, Ian P and Dupuis, Jos{\'e}e and Tobin, Martin D and London, Stephanie J} } @article {8016, title = {Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Apr 15}, pages = {491-501}, abstract = {

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 {\texttimes} 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 {\texttimes} 10(-4), Bonferroni corrected), of which six reached P < 5 {\texttimes} 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

}, keywords = {Bone Density, Computational Biology, European Continental Ancestry Group, Extracellular Matrix Proteins, Female, Femur Neck, Fractures, Bone, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glycoproteins, Humans, Intercellular Signaling Peptides and Proteins, Low Density Lipoprotein Receptor-Related Protein-5, Lumbar Vertebrae, Male, Mitochondrial Membrane Transport Proteins, Osteoporosis, Phosphoproteins, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Spectrin}, issn = {1546-1718}, doi = {10.1038/ng.2249}, author = {Estrada, Karol and Styrkarsdottir, Unnur and Evangelou, Evangelos and Hsu, Yi-Hsiang and Duncan, Emma L and Ntzani, Evangelia E and Oei, Ling and Albagha, Omar M E and Amin, Najaf and Kemp, John P and Koller, Daniel L and Li, Guo and Liu, Ching-Ti and Minster, Ryan L and Moayyeri, Alireza and Vandenput, Liesbeth and Willner, Dana and Xiao, Su-Mei and Yerges-Armstrong, Laura M and Zheng, Hou-Feng and Alonso, Nerea and Eriksson, Joel and Kammerer, Candace M and Kaptoge, Stephen K and Leo, Paul J and Thorleifsson, Gudmar and Wilson, Scott G and Wilson, James F and Aalto, Ville and Alen, Markku and Aragaki, Aaron K and Aspelund, Thor and Center, Jacqueline R and Dailiana, Zoe and Duggan, David J and Garcia, Melissa and Garc{\'\i}a-Giralt, Natalia and Giroux, Sylvie and Hallmans, G{\"o}ran and Hocking, Lynne J and Husted, Lise Bjerre and Jameson, Karen A and Khusainova, Rita and Kim, Ghi Su and Kooperberg, Charles and Koromila, Theodora and Kruk, Marcin and Laaksonen, Marika and LaCroix, Andrea Z and Lee, Seung Hun and Leung, Ping C and Lewis, Joshua R and Masi, Laura and Mencej-Bedrac, Simona and Nguyen, Tuan V and Nogues, Xavier and Patel, Millan S and Prezelj, Janez and Rose, Lynda M and Scollen, Serena and Siggeirsdottir, Kristin and Smith, Albert V and Svensson, Olle and Trompet, Stella and Trummer, Olivia and van Schoor, Natasja M and Woo, Jean and Zhu, Kun and Balcells, Susana and Brandi, Maria Luisa and Buckley, Brendan M and Cheng, Sulin and Christiansen, Claus and Cooper, Cyrus and Dedoussis, George and Ford, Ian and Frost, Morten and Goltzman, David and Gonz{\'a}lez-Mac{\'\i}as, Jes{\'u}s and K{\"a}h{\"o}nen, Mika and Karlsson, Magnus and Khusnutdinova, Elza and Koh, Jung-Min and Kollia, Panagoula and Langdahl, Bente Lomholt and Leslie, William D and Lips, Paul and Ljunggren, Osten and Lorenc, Roman S and Marc, Janja and Mellstr{\"o}m, Dan and Obermayer-Pietsch, Barbara and Olmos, Jos{\'e} M and Pettersson-Kymmer, Ulrika and Reid, David M and Riancho, Jos{\'e} A and Ridker, Paul M and Rousseau, Fran{\c c}ois and Slagboom, P Eline and Tang, Nelson L S and Urreizti, Roser and Van Hul, Wim and Viikari, Jorma and Zarrabeitia, Mar{\'\i}a T and Aulchenko, Yurii S and Castano-Betancourt, Martha and Grundberg, Elin and Herrera, Lizbeth and Ingvarsson, Thorvaldur and Johannsdottir, Hrefna and Kwan, Tony and Li, Rui and Luben, Robert and Medina-G{\'o}mez, Carolina and Palsson, Stefan Th and Reppe, Sjur and Rotter, Jerome I and Sigurdsson, Gunnar and van Meurs, Joyce B J and Verlaan, Dominique and Williams, Frances M K and Wood, Andrew R and Zhou, Yanhua and Gautvik, Kaare M and Pastinen, Tomi and Raychaudhuri, Soumya and Cauley, Jane A and Chasman, Daniel I and Clark, Graeme R and Cummings, Steven R and Danoy, Patrick and Dennison, Elaine M and Eastell, Richard and Eisman, John A and Gudnason, Vilmundur and Hofman, Albert and Jackson, Rebecca D and Jones, Graeme and Jukema, J Wouter and Khaw, Kay-Tee and Lehtim{\"a}ki, Terho and Liu, Yongmei and Lorentzon, Mattias and McCloskey, Eugene and Mitchell, Braxton D and Nandakumar, Kannabiran and Nicholson, Geoffrey C and Oostra, Ben A and Peacock, Munro and Pols, Huibert A P and Prince, Richard L and Raitakari, Olli and Reid, Ian R and Robbins, John and Sambrook, Philip N and Sham, Pak Chung and Shuldiner, Alan R and Tylavsky, Frances A and van Duijn, Cornelia M and Wareham, Nick J and Cupples, L Adrienne and Econs, Michael J and Evans, David M and Harris, Tamara B and Kung, Annie Wai Chee and Psaty, Bruce M and Reeve, Jonathan and Spector, Timothy D and Streeten, Elizabeth A and Zillikens, M Carola and Thorsteinsdottir, Unnur and Ohlsson, Claes and Karasik, David and Richards, J Brent and Brown, Matthew A and Stefansson, Kari and Uitterlinden, Andr{\'e} G and Ralston, Stuart H and Ioannidis, John P A and Kiel, Douglas P and Rivadeneira, Fernando} } @article {6075, title = {Genome-wide association analyses identify 18 new loci associated with serum urate concentrations.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Feb}, pages = {145-54}, abstract = {

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

}, keywords = {Analysis of Variance, European Continental Ancestry Group, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Glucose, Gout, Humans, Inhibins, Polymorphism, Single Nucleotide, Signal Transduction, Uric Acid}, issn = {1546-1718}, doi = {10.1038/ng.2500}, author = {K{\"o}ttgen, Anna and Albrecht, Eva and Teumer, Alexander and Vitart, Veronique and Krumsiek, Jan and Hundertmark, Claudia and Pistis, Giorgio and Ruggiero, Daniela and O{\textquoteright}Seaghdha, Conall M and Haller, Toomas and Yang, Qiong and Tanaka, Toshiko and Johnson, Andrew D and Kutalik, Zolt{\'a}n and Smith, Albert V and Shi, Julia and Struchalin, Maksim and Middelberg, Rita P S and Brown, Morris J and Gaffo, Angelo L and Pirastu, Nicola and Li, Guo and Hayward, Caroline and Zemunik, Tatijana and Huffman, Jennifer and Yengo, Loic and Zhao, Jing Hua and Demirkan, Ayse and Feitosa, Mary F and Liu, Xuan and Malerba, Giovanni and Lopez, Lorna M and van der Harst, Pim and Li, Xinzhong and Kleber, Marcus E and Hicks, Andrew A and Nolte, Ilja M and Johansson, Asa and Murgia, Federico and Wild, Sarah H and Bakker, Stephan J L and Peden, John F and Dehghan, Abbas and Steri, Maristella and Tenesa, Albert and Lagou, Vasiliki and Salo, Perttu and Mangino, Massimo and Rose, Lynda M and Lehtim{\"a}ki, Terho and Woodward, Owen M and Okada, Yukinori and Tin, Adrienne and M{\"u}ller, Christian and Oldmeadow, Christopher and Putku, Margus and Czamara, Darina and Kraft, Peter and Frogheri, Laura and Thun, Gian Andri and Grotevendt, Anne and Gislason, Gauti Kjartan and Harris, Tamara B and Launer, Lenore J and McArdle, Patrick and Shuldiner, Alan R and Boerwinkle, Eric and Coresh, Josef and Schmidt, Helena and Schallert, Michael and Martin, Nicholas G and Montgomery, Grant W and Kubo, Michiaki and Nakamura, Yusuke and Tanaka, Toshihiro and Munroe, Patricia B and Samani, Nilesh J and Jacobs, David R and Liu, Kiang and D{\textquoteright}Adamo, Pio and Ulivi, Sheila and Rotter, Jerome I and Psaty, Bruce M and Vollenweider, Peter and Waeber, G{\'e}rard and Campbell, Susan and Devuyst, Olivier and Navarro, Pau and Kolcic, Ivana and Hastie, Nicholas and Balkau, Beverley and Froguel, Philippe and Esko, T{\~o}nu and Salumets, Andres and Khaw, Kay Tee and Langenberg, Claudia and Wareham, Nicholas J and Isaacs, Aaron and Kraja, Aldi and Zhang, Qunyuan and Wild, Philipp S and Scott, Rodney J and Holliday, Elizabeth G and Org, Elin and Viigimaa, Margus and Bandinelli, Stefania and Metter, Jeffrey E and Lupo, Antonio and Trabetti, Elisabetta and Sorice, Rossella and D{\"o}ring, Angela and Lattka, Eva and Strauch, Konstantin and Theis, Fabian and Waldenberger, Melanie and Wichmann, H-Erich and Davies, Gail and Gow, Alan J and Bruinenberg, Marcel and Stolk, Ronald P and Kooner, Jaspal S and Zhang, Weihua and Winkelmann, Bernhard R and Boehm, Bernhard O and Lucae, Susanne and Penninx, Brenda W and Smit, Johannes H and Curhan, Gary and Mudgal, Poorva and Plenge, Robert M and Portas, Laura and Persico, Ivana and Kirin, Mirna and Wilson, James F and Mateo Leach, Irene and van Gilst, Wiek H and Goel, Anuj and Ongen, Halit and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Imboden, Medea and von Eckardstein, Arnold and Cucca, Francesco and Nagaraja, Ramaiah and Piras, Maria Grazia and Nauck, Matthias and Schurmann, Claudia and Budde, Kathrin and Ernst, Florian and Farrington, Susan M and Theodoratou, Evropi and Prokopenko, Inga and Stumvoll, Michael and Jula, Antti and Perola, Markus and Salomaa, Veikko and Shin, So-Youn and Spector, Tim D and Sala, Cinzia and Ridker, Paul M and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Hengstenberg, Christian and Nelson, Christopher P and Meschia, James F and Nalls, Michael A and Sharma, Pankaj and Singleton, Andrew B and Kamatani, Naoyuki and Zeller, Tanja and Burnier, Michel and Attia, John and Laan, Maris and Klopp, Norman and Hillege, Hans L and Kloiber, Stefan and Choi, Hyon and Pirastu, Mario and Tore, Silvia and Probst-Hensch, Nicole M and V{\"o}lzke, Henry and Gudnason, Vilmundur and Parsa, Afshin and Schmidt, Reinhold and Whitfield, John B and Fornage, Myriam and Gasparini, Paolo and Siscovick, David S and Polasek, Ozren and Campbell, Harry and Rudan, Igor and Bouatia-Naji, Nabila and Metspalu, Andres and Loos, Ruth J F and van Duijn, Cornelia M and Borecki, Ingrid B and Ferrucci, Luigi and Gambaro, Giovanni and Deary, Ian J and Wolffenbuttel, Bruce H R and Chambers, John C and M{\"a}rz, Winfried and Pramstaller, Peter P and Snieder, Harold and Gyllensten, Ulf and Wright, Alan F and Navis, Gerjan and Watkins, Hugh and Witteman, Jacqueline C M and Sanna, Serena and Schipf, Sabine and Dunlop, Malcolm G and T{\"o}njes, Anke and Ripatti, Samuli and Soranzo, Nicole and Toniolo, Daniela and Chasman, Daniel I and Raitakari, Olli and Kao, W H Linda and Ciullo, Marina and Fox, Caroline S and Caulfield, Mark and Bochud, Murielle and Gieger, Christian} } @article {6070, title = {A genome-wide association study of depressive symptoms.}, journal = {Biol Psychiatry}, volume = {73}, year = {2013}, month = {2013 Apr 01}, pages = {667-78}, abstract = {

BACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.

METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1{\texttimes}10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.

RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05{\texttimes}10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19{\texttimes}10(-3)). This 5q21 region reached genome-wide significance (p = 4.78{\texttimes}10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258).

CONCLUSIONS: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

}, keywords = {Aged, Aged, 80 and over, Chromosomes, Human, Pair 5, Depression, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1873-2402}, doi = {10.1016/j.biopsych.2012.09.033}, author = {Hek, Karin and Demirkan, Ayse and Lahti, Jari and Terracciano, Antonio and Teumer, Alexander and Cornelis, Marilyn C and Amin, Najaf and Bakshis, Erin and Baumert, Jens and Ding, Jingzhong and Liu, Yongmei and Marciante, Kristin and Meirelles, Osorio and Nalls, Michael A and Sun, Yan V and Vogelzangs, Nicole and Yu, Lei and Bandinelli, Stefania and Benjamin, Emelia J and Bennett, David A and Boomsma, Dorret and Cannas, Alessandra and Coker, Laura H and de Geus, Eco and De Jager, Philip L and Diez-Roux, Ana V and Purcell, Shaun and Hu, Frank B and Rimma, Eric B and Hunter, David J and Jensen, Majken K and Curhan, Gary and Rice, Kenneth and Penman, Alan D and Rotter, Jerome I and Sotoodehnia, Nona and Emeny, Rebecca and Eriksson, Johan G and Evans, Denis A and Ferrucci, Luigi and Fornage, Myriam and Gudnason, Vilmundur and Hofman, Albert and Illig, Thomas and Kardia, Sharon and Kelly-Hayes, Margaret and Koenen, Karestan and Kraft, Peter and Kuningas, Maris and Massaro, Joseph M and Melzer, David and Mulas, Antonella and Mulder, Cornelis L and Murray, Anna and Oostra, Ben A and Palotie, Aarno and Penninx, Brenda and Petersmann, Astrid and Pilling, Luke C and Psaty, Bruce and Rawal, Rajesh and Reiman, Eric M and Schulz, Andrea and Shulman, Joshua M and Singleton, Andrew B and Smith, Albert V and Sutin, Angelina R and Uitterlinden, Andr{\'e} G and V{\"o}lzke, Henry and Widen, Elisabeth and Yaffe, Kristine and Zonderman, Alan B and Cucca, Francesco and Harris, Tamara and Ladwig, Karl-Heinz and Llewellyn, David J and R{\"a}ikk{\"o}nen, Katri and Tanaka, Toshiko and van Duijn, Cornelia M and Grabe, Hans J and Launer, Lenore J and Lunetta, Kathryn L and Mosley, Thomas H and Newman, Anne B and Tiemeier, Henning and Murabito, Joanne} } @article {6599, title = {Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Jul 03}, pages = {24-38}, abstract = {

Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p <= 5 {\texttimes} 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 {\texttimes} 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

}, keywords = {Adolescent, Adult, Age Factors, Aged, Blood Pressure, Cohort Studies, Humans, Middle Aged, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.05.010}, author = {Simino, Jeannette and Shi, Gang and Bis, Joshua C and Chasman, Daniel I and Ehret, Georg B and Gu, Xiangjun and Guo, Xiuqing and Hwang, Shih-Jen and Sijbrands, Eric and Smith, Albert V and Verwoert, Germaine C and Bragg-Gresham, Jennifer L and Cadby, Gemma and Chen, Peng and Cheng, Ching-Yu and Corre, Tanguy and de Boer, Rudolf A and Goel, Anuj and Johnson, Toby and Khor, Chiea-Chuen and Llu{\'\i}s-Ganella, Carla and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Sim, Xueling and S{\~o}ber, Siim and van der Most, Peter J and Verweij, Niek and Zhao, Jing Hua and Amin, Najaf and Boerwinkle, Eric and Bouchard, Claude and Dehghan, Abbas and Eiriksdottir, Gudny and Elosua, Roberto and Franco, Oscar H and Gieger, Christian and Harris, Tamara B and Hercberg, Serge and Hofman, Albert and James, Alan L and Johnson, Andrew D and K{\"a}h{\"o}nen, Mika and Khaw, Kay-Tee and Kutalik, Zolt{\'a}n and Larson, Martin G and Launer, Lenore J and Li, Guo and Liu, Jianjun and Liu, Kiang and Morrison, Alanna C and Navis, Gerjan and Ong, Rick Twee-Hee and Papanicolau, George J and Penninx, Brenda W and Psaty, Bruce M and Raffel, Leslie J and Raitakari, Olli T and Rice, Kenneth and Rivadeneira, Fernando and Rose, Lynda M and Sanna, Serena and Scott, Robert A and Siscovick, David S and Stolk, Ronald P and Uitterlinden, Andr{\'e} G and Vaidya, Dhananjay and van der Klauw, Melanie M and Vasan, Ramachandran S and Vithana, Eranga Nishanthie and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Watkins, Hugh and Young, Terri L and Aung, Tin and Bochud, Murielle and Farrall, Martin and Hartman, Catharina A and Laan, Maris and Lakatta, Edward G and Lehtim{\"a}ki, Terho and Loos, Ruth J F and Lucas, Gavin and Meneton, Pierre and Palmer, Lyle J and Rettig, Rainer and Snieder, Harold and Tai, E Shyong and Teo, Yik-Ying and van der Harst, Pim and Wareham, Nicholas J and Wijmenga, Cisca and Wong, Tien Yin and Fornage, Myriam and Gudnason, Vilmundur and Levy, Daniel and Palmas, Walter and Ridker, Paul M and Rotter, Jerome I and van Duijn, Cornelia M and Witteman, Jacqueline C M and Chakravarti, Aravinda and Rao, Dabeeru C} } @article {6617, title = {Gene-wide analysis detects two new susceptibility genes for Alzheimer{\textquoteright}s disease.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e94661}, abstract = {

BACKGROUND: Alzheimer{\textquoteright}s disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer{\textquoteright}s Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer{\textquoteright}s cases and 48,466 controls.

PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4{\texttimes}10-6) and 14 (IGHV1-67 p = 7.9{\texttimes}10-8) which indexed novel susceptibility loci.

SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer{\textquoteright}s disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer{\textquoteright}s disease.

}, keywords = {Alzheimer Disease, Carrier Proteins, Case-Control Studies, Genome-Wide Association Study, Heat-Shock Proteins, Humans, Polymorphism, Single Nucleotide, Receptors, Antigen, B-Cell}, issn = {1932-6203}, doi = {10.1371/journal.pone.0094661}, author = {Escott-Price, Valentina and Bellenguez, C{\'e}line and Wang, Li-San and Choi, Seung-Hoan and Harold, Denise and Jones, Lesley and Holmans, Peter and Gerrish, Amy and Vedernikov, Alexey and Richards, Alexander and DeStefano, Anita L and Lambert, Jean-Charles and Ibrahim-Verbaas, Carla A and Naj, Adam C and Sims, Rebecca and Jun, Gyungah and Bis, Joshua C and Beecham, Gary W and Grenier-Boley, Benjamin and Russo, Giancarlo and Thornton-Wells, Tricia A and Denning, Nicola and Smith, Albert V and Chouraki, Vincent and Thomas, Charlene and Ikram, M Arfan and Zelenika, Diana and Vardarajan, Badri N and Kamatani, Yoichiro and Lin, Chiao-Feng and Schmidt, Helena and Kunkle, Brian and Dunstan, Melanie L and Vronskaya, Maria and Johnson, Andrew D and Ruiz, Agustin and Bihoreau, Marie-Th{\'e}r{\`e}se and Reitz, Christiane and Pasquier, Florence and Hollingworth, Paul and Hanon, Olivier and Fitzpatrick, Annette L and Buxbaum, Joseph D and Campion, Dominique and Crane, Paul K and Baldwin, Clinton and Becker, Tim and Gudnason, Vilmundur and Cruchaga, Carlos and Craig, David and Amin, Najaf and Berr, Claudine and Lopez, Oscar L and De Jager, Philip L and Deramecourt, Vincent and Johnston, Janet A and Evans, Denis and Lovestone, Simon and Letenneur, Luc and Hernandez, Isabel and Rubinsztein, David C and Eiriksdottir, Gudny and Sleegers, Kristel and Goate, Alison M and Fi{\'e}vet, Nathalie and Huentelman, Matthew J and Gill, Michael and Brown, Kristelle and Kamboh, M Ilyas and Keller, Lina and Barberger-Gateau, Pascale and McGuinness, Bernadette and Larson, Eric B and Myers, Amanda J and Dufouil, Carole and Todd, Stephen and Wallon, David and Love, Seth and Rogaeva, Ekaterina and Gallacher, John and George-Hyslop, Peter St and Clarimon, Jordi and Lleo, Alberto and Bayer, Anthony and Tsuang, Debby W and Yu, Lei and Tsolaki, Magda and Boss{\`u}, Paola and Spalletta, Gianfranco and Proitsi, Petra and Collinge, John and Sorbi, Sandro and Garcia, Florentino Sanchez and Fox, Nick C and Hardy, John and Naranjo, Maria Candida Deniz and Bosco, Paolo and Clarke, Robert and Brayne, Carol and Galimberti, Daniela and Scarpini, Elio and Bonuccelli, Ubaldo and Mancuso, Michelangelo and Siciliano, Gabriele and Moebus, Susanne and Mecocci, Patrizia and Zompo, Maria Del and Maier, Wolfgang and Hampel, Harald and Pilotto, Alberto and Frank-Garc{\'\i}a, Ana and Panza, Francesco and Solfrizzi, Vincenzo and Caffarra, Paolo and Nacmias, Benedetta and Perry, William and Mayhaus, Manuel and Lannfelt, Lars and Hakonarson, Hakon and Pichler, Sabrina and Carrasquillo, Minerva M and Ingelsson, Martin and Beekly, Duane and Alvarez, Victoria and Zou, Fanggeng and Valladares, Otto and Younkin, Steven G and Coto, Eliecer and Hamilton-Nelson, Kara L and Gu, Wei and Razquin, Cristina and Pastor, Pau and Mateo, Ignacio and Owen, Michael J and Faber, Kelley M and Jonsson, Palmi V and Combarros, Onofre and O{\textquoteright}Donovan, Michael C and Cantwell, Laura B and Soininen, Hilkka and Blacker, Deborah and Mead, Simon and Mosley, Thomas H and Bennett, David A and Harris, Tamara B and Fratiglioni, Laura and Holmes, Clive and de Bruijn, Renee F A G and Passmore, Peter and Montine, Thomas J and Bettens, Karolien and Rotter, Jerome I and Brice, Alexis and Morgan, Kevin and Foroud, Tatiana M and Kukull, Walter A and Hannequin, Didier and Powell, John F and Nalls, Michael A and Ritchie, Karen and Lunetta, Kathryn L and Kauwe, John S K and Boerwinkle, Eric and Riemenschneider, Matthias and Boada, Merce and Hiltunen, Mikko and Martin, Eden R and Schmidt, Reinhold and Rujescu, Dan and Dartigues, Jean-Fran{\c c}ois and Mayeux, Richard and Tzourio, Christophe and Hofman, Albert and N{\"o}then, Markus M and Graff, Caroline and Psaty, Bruce M and Haines, Jonathan L and Lathrop, Mark and Pericak-Vance, Margaret A and Launer, Lenore J and Van Broeckhoven, Christine and Farrer, Lindsay A and van Duijn, Cornelia M and Ramirez, Alfredo and Seshadri, Sudha and Schellenberg, Gerard D and Amouyel, Philippe and Williams, Julie} } @article {6550, title = {GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {70}, year = {2015}, month = {2015 Jan}, pages = {110-8}, abstract = {

BACKGROUND: The genetic contribution to longevity in humans has been estimated to range from 15\% to 25\%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.

METHODS: We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age >=90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.

RESULTS: In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 {\texttimes} 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 {\texttimes} 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85{\texttimes}10(-10)).

CONCLUSIONS: We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages >=90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.

}, keywords = {Aged, Aged, 80 and over, Apolipoproteins E, Cell Adhesion Molecules, Cohort Studies, Female, Forkhead Box Protein O3, Forkhead Transcription Factors, Genome-Wide Association Study, Humans, Longevity, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Kainic Acid}, issn = {1758-535X}, doi = {10.1093/gerona/glu166}, author = {Broer, Linda and Buchman, Aron S and Deelen, Joris and Evans, Daniel S and Faul, Jessica D and Lunetta, Kathryn L and Sebastiani, Paola and Smith, Jennifer A and Smith, Albert V and Tanaka, Toshiko and Yu, Lei and Arnold, Alice M and Aspelund, Thor and Benjamin, Emelia J and De Jager, Philip L and Eirkisdottir, Gudny and Evans, Denis A and Garcia, Melissa E and Hofman, Albert and Kaplan, Robert C and Kardia, Sharon L R and Kiel, Douglas P and Oostra, Ben A and Orwoll, Eric S and Parimi, Neeta and Psaty, Bruce M and Rivadeneira, Fernando and Rotter, Jerome I and Seshadri, Sudha and Singleton, Andrew and Tiemeier, Henning and Uitterlinden, Andr{\'e} G and Zhao, Wei and Bandinelli, Stefania and Bennett, David A and Ferrucci, Luigi and Gudnason, Vilmundur and Harris, Tamara B and Karasik, David and Launer, Lenore J and Perls, Thomas T and Slagboom, P Eline and Tranah, Gregory J and Weir, David R and Newman, Anne B and van Duijn, Cornelia M and Murabito, Joanne M} } @article {7142, title = {GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium.}, journal = {Aging Cell}, volume = {15}, year = {2016}, month = {2016 Oct}, pages = {792-800}, abstract = {

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27~581 individuals of European descent over 65~years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5~{\texttimes}~10(-8) ) and 39 suggestive (P-value< 5~{\texttimes}~10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β~=~0.47, SE~=~0.08, P-value~=~5.20~{\texttimes}~10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

}, issn = {1474-9726}, doi = {10.1111/acel.12468}, author = {Matteini, Amy M and Tanaka, Toshiko and Karasik, David and Atzmon, Gil and Chou, Wen-Chi and Eicher, John D and Johnson, Andrew D and Arnold, Alice M and Callisaya, Michele L and Davies, Gail and Evans, Daniel S and Holtfreter, Birte and Lohman, Kurt and Lunetta, Kathryn L and Mangino, Massimo and Smith, Albert V and Smith, Jennifer A and Teumer, Alexander and Yu, Lei and Arking, Dan E and Buchman, Aron S and Chibinik, Lori B and De Jager, Philip L and Evans, Denis A and Faul, Jessica D and Garcia, Melissa E and Gillham-Nasenya, Irina and Gudnason, Vilmundur and Hofman, Albert and Hsu, Yi-Hsiang and Ittermann, Till and Lahousse, Lies and Liewald, David C and Liu, Yongmei and Lopez, Lorna and Rivadeneira, Fernando and Rotter, Jerome I and Siggeirsdottir, Kristin and Starr, John M and Thomson, Russell and Tranah, Gregory J and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Weir, David R and Yaffe, Kristine and Zhao, Wei and Zhuang, Wei Vivian and Zmuda, Joseph M and Bennett, David A and Cummings, Steven R and Deary, Ian J and Ferrucci, Luigi and Harris, Tamara B and Kardia, Sharon L R and Kocher, Thomas and Kritchevsky, Stephen B and Psaty, Bruce M and Seshadri, Sudha and Spector, Timothy D and Srikanth, Velandai K and Windham, B Gwen and Zillikens, M Carola and Newman, Anne B and Walston, Jeremy D and Kiel, Douglas P and Murabito, Joanne M} } @article {7590, title = {Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.}, journal = {Diabetes}, volume = {66}, year = {2017}, month = {2017 12}, pages = {3130-3141}, abstract = {

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.

}, keywords = {Aged, Diabetic Retinopathy, Female, Genome-Wide Association Study, Humans, Lipids, Male, Mendelian Randomization Analysis, Middle Aged, Polymorphism, Single Nucleotide, Risk}, issn = {1939-327X}, doi = {10.2337/db17-0398}, author = {Sobrin, Lucia and Chong, Yong He and Fan, Qiao and Gan, Alfred and Stanwyck, Lynn K and Kaidonis, Georgia and Craig, Jamie E and Kim, Jihye and Liao, Wen-Ling and Huang, Yu-Chuen and Lee, Wen-Jane and Hung, Yi-Jen and Guo, Xiuqing and Hai, Yang and Ipp, Eli and Pollack, Samuela and Hancock, Heather and Price, Alkes and Penman, Alan and Mitchell, Paul and Liew, Gerald and Smith, Albert V and Gudnason, Vilmundur and Tan, Gavin and Klein, Barbara E K and Kuo, Jane and Li, Xiaohui and Christiansen, Mark W and Psaty, Bruce M and Sandow, Kevin and Jensen, Richard A and Klein, Ronald and Cotch, Mary Frances and Wang, Jie Jin and Jia, Yucheng and Chen, Ching J and Chen, Yii-Der Ida and Rotter, Jerome I and Tsai, Fuu-Jen and Hanis, Craig L and Burdon, Kathryn P and Wong, Tien Yin and Cheng, Ching-Yu} } @article {7353, title = {A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.}, journal = {J Med Genet}, volume = {54}, year = {2017}, month = {2017 May}, pages = {313-323}, abstract = {

BACKGROUND: Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.

METHODS AND RESULTS: We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e(-9)) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e(-8)). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e(-8)). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.

CONCLUSIONS: Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2016-104112}, author = {Noordam, Raymond and Sitlani, Colleen M and Avery, Christy L and Stewart, James D and Gogarten, Stephanie M and Wiggins, Kerri L and Trompet, Stella and Warren, Helen R and Sun, Fangui and Evans, Daniel S and Li, Xiaohui and Li, Jin and Smith, Albert V and Bis, Joshua C and Brody, Jennifer A and Busch, Evan L and Caulfield, Mark J and Chen, Yii-der I and Cummings, Steven R and Cupples, L Adrienne and Duan, Qing and Franco, Oscar H and M{\'e}ndez-Gir{\'a}ldez, R{\'a}ul and Harris, Tamara B and Heckbert, Susan R and van Heemst, Diana and Hofman, Albert and Floyd, James S and Kors, Jan A and Launer, Lenore J and Li, Yun and Li-Gao, Ruifang and Lange, Leslie A and Lin, Henry J and de Mutsert, Ren{\'e}e and Napier, Melanie D and Newton-Cheh, Christopher and Poulter, Neil and Reiner, Alexander P and Rice, Kenneth M and Roach, Jeffrey and Rodriguez, Carlos J and Rosendaal, Frits R and Sattar, Naveed and Sever, Peter and Seyerle, Amanda A and Slagboom, P Eline and Soliman, Elsayed Z and Sotoodehnia, Nona and Stott, David J and St{\"u}rmer, Til and Taylor, Kent D and Thornton, Timothy A and Uitterlinden, Andr{\'e} G and Wilhelmsen, Kirk C and Wilson, James G and Gudnason, Vilmundur and Jukema, J Wouter and Laurie, Cathy C and Liu, Yongmei and Mook-Kanamori, Dennis O and Munroe, Patricia B and Rotter, Jerome I and Vasan, Ramachandran S and Psaty, Bruce M and Stricker, Bruno H and Whitsel, Eric A} } @article {7364, title = {Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Jan 05}, pages = {51-63}, abstract = {

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in~vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.11.016}, author = {van Rooij, Frank J A and Qayyum, Rehan and Smith, Albert V and Zhou, Yi and Trompet, Stella and Tanaka, Toshiko and Keller, Margaux F and Chang, Li-Ching and Schmidt, Helena and Yang, Min-Lee and Chen, Ming-Huei and Hayes, James and Johnson, Andrew D and Yanek, Lisa R and Mueller, Christian and Lange, Leslie and Floyd, James S and Ghanbari, Mohsen and Zonderman, Alan B and Jukema, J Wouter and Hofman, Albert and van Duijn, Cornelia M and Desch, Karl C and Saba, Yasaman and Ozel, Ayse B and Snively, Beverly M and Wu, Jer-Yuarn and Schmidt, Reinhold and Fornage, Myriam and Klein, Robert J and Fox, Caroline S and Matsuda, Koichi and Kamatani, Naoyuki and Wild, Philipp S and Stott, David J and Ford, Ian and Slagboom, P Eline and Yang, Jaden and Chu, Audrey Y and Lambert, Amy J and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Hofer, Edith and Ginsburg, David and Hu, Bella and Keating, Brendan and Schick, Ursula M and Brody, Jennifer A and Li, Jun Z and Chen, Zhao and Zeller, Tanja and Guralnik, Jack M and Chasman, Daniel I and Peters, Luanne L and Kubo, Michiaki and Becker, Diane M and Li, Jin and Eiriksdottir, Gudny and Rotter, Jerome I and Levy, Daniel and Grossmann, Vera and Patel, Kushang V and Chen, Chien-Hsiun and Ridker, Paul M and Tang, Hua and Launer, Lenore J and Rice, Kenneth M and Li-Gao, Ruifang and Ferrucci, Luigi and Evans, Michelle K and Choudhuri, Avik and Trompouki, Eirini and Abraham, Brian J and Yang, Song and Takahashi, Atsushi and Kamatani, Yoichiro and Kooperberg, Charles and Harris, Tamara B and Jee, Sun Ha and Coresh, Josef and Tsai, Fuu-Jen and Longo, Dan L and Chen, Yuan-Tsong and Felix, Janine F and Yang, Qiong and Psaty, Bruce M and Boerwinkle, Eric and Becker, Lewis C and Mook-Kanamori, Dennis O and Wilson, James G and Gudnason, Vilmundur and O{\textquoteright}Donnell, Christopher J and Dehghan, Abbas and Cupples, L Adrienne and Nalls, Michael A and Morris, Andrew P and Okada, Yukinori and Reiner, Alexander P and Zon, Leonard I and Ganesh, Santhi K} } @article {7845, title = {Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Oct}, pages = {1412-1425}, abstract = {

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0205-x}, author = {Evangelou, Evangelos and Warren, Helen R and Mosen-Ansorena, David and Mifsud, Borbala and Pazoki, Raha and Gao, He and Ntritsos, Georgios and Dimou, Niki and Cabrera, Claudia P and Karaman, Ibrahim and Ng, Fu Liang and Evangelou, Marina and Witkowska, Katarzyna and Tzanis, Evan and Hellwege, Jacklyn N and Giri, Ayush and Velez Edwards, Digna R and Sun, Yan V and Cho, Kelly and Gaziano, J Michael and Wilson, Peter W F and Tsao, Philip S and Kovesdy, Csaba P and Esko, T{\~o}nu and M{\"a}gi, Reedik and Milani, Lili and Almgren, Peter and Boutin, Thibaud and Debette, Stephanie and Ding, Jun and Giulianini, Franco and Holliday, Elizabeth G and Jackson, Anne U and Li-Gao, Ruifang and Lin, Wei-Yu and Luan, Jian{\textquoteright}an and Mangino, Massimo and Oldmeadow, Christopher and Prins, Bram Peter and Qian, Yong and Sargurupremraj, Muralidharan and Shah, Nabi and Surendran, Praveen and Th{\'e}riault, S{\'e}bastien and Verweij, Niek and Willems, Sara M and Zhao, Jing-Hua and Amouyel, Philippe and Connell, John and de Mutsert, Ren{\'e}e and Doney, Alex S F and Farrall, Martin and Menni, Cristina and Morris, Andrew D and Noordam, Raymond and Par{\'e}, Guillaume and Poulter, Neil R and Shields, Denis C and Stanton, Alice and Thom, Simon and Abecasis, Goncalo and Amin, Najaf and Arking, Dan E and Ayers, Kristin L and Barbieri, Caterina M and Batini, Chiara and Bis, Joshua C and Blake, Tineka and Bochud, Murielle and Boehnke, Michael and Boerwinkle, Eric and Boomsma, Dorret I and Bottinger, Erwin P and Braund, Peter S and Brumat, Marco and Campbell, Archie and Campbell, Harry and Chakravarti, Aravinda and Chambers, John C and Chauhan, Ganesh and Ciullo, Marina and Cocca, Massimiliano and Collins, Francis and Cordell, Heather J and Davies, Gail and Borst, Martin H de and Geus, Eco J de and Deary, Ian J and Deelen, Joris and del Greco M, Fabiola and Demirkale, Cumhur Yusuf and D{\"o}rr, Marcus and Ehret, Georg B and Elosua, Roberto and Enroth, Stefan and Erzurumluoglu, A Mesut and Ferreira, Teresa and Fr{\r a}nberg, Mattias and Franco, Oscar H and Gandin, Ilaria and Gasparini, Paolo and Giedraitis, Vilmantas and Gieger, Christian and Girotto, Giorgia and Goel, Anuj and Gow, Alan J and Gudnason, Vilmundur and Guo, Xiuqing and Gyllensten, Ulf and Hamsten, Anders and Harris, Tamara B and Harris, Sarah E and Hartman, Catharina A and Havulinna, Aki S and Hicks, Andrew A and Hofer, Edith and Hofman, Albert and Hottenga, Jouke-Jan and Huffman, Jennifer E and Hwang, Shih-Jen and Ingelsson, Erik and James, Alan and Jansen, Rick and Jarvelin, Marjo-Riitta and Joehanes, Roby and Johansson, Asa and Johnson, Andrew D and Joshi, Peter K and Jousilahti, Pekka and Jukema, J Wouter and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Keavney, Bernard D and Khaw, Kay-Tee and Knekt, Paul and Knight, Joanne and Kolcic, Ivana and Kooner, Jaspal S and Koskinen, Seppo and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Laan, Maris and Larson, Marty and Launer, Lenore J and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Liewald, David C M and Lin, Li and Lind, Lars and Lindgren, Cecilia M and Liu, Yongmei and Loos, Ruth J F and Lopez, Lorna M and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Mamasoula, Chrysovalanto and Marrugat, Jaume and Marten, Jonathan and Milaneschi, Yuri and Morgan, Anna and Morris, Andrew P and Morrison, Alanna C and Munson, Peter J and Nalls, Mike A and Nandakumar, Priyanka and Nelson, Christopher P and Niiranen, Teemu and Nolte, Ilja M and Nutile, Teresa and Oldehinkel, Albertine J and Oostra, Ben A and O{\textquoteright}Reilly, Paul F and Org, Elin and Padmanabhan, Sandosh and Palmas, Walter and Palotie, Aarno and Pattie, Alison and Penninx, Brenda W J H and Perola, Markus and Peters, Annette and Polasek, Ozren and Pramstaller, Peter P and Nguyen, Quang Tri and Raitakari, Olli T and Ren, Meixia and Rettig, Rainer and Rice, Kenneth and Ridker, Paul M and Ried, Janina S and Riese, Harri{\"e}tte and Ripatti, Samuli and Robino, Antonietta and Rose, Lynda M and Rotter, Jerome I and Rudan, Igor and Ruggiero, Daniela and Saba, Yasaman and Sala, Cinzia F and Salomaa, Veikko and Samani, Nilesh J and Sarin, Antti-Pekka and Schmidt, Reinhold and Schmidt, Helena and Shrine, Nick and Siscovick, David and Smith, Albert V and Snieder, Harold and S{\~o}ber, Siim and Sorice, Rossella and Starr, John M and Stott, David J and Strachan, David P and Strawbridge, Rona J and Sundstr{\"o}m, Johan and Swertz, Morris A and Taylor, Kent D and Teumer, Alexander and Tobin, Martin D and Tomaszewski, Maciej and Toniolo, Daniela and Traglia, Michela and Trompet, Stella and Tuomilehto, Jaakko and Tzourio, Christophe and Uitterlinden, Andr{\'e} G and Vaez, Ahmad and van der Most, Peter J and van Duijn, Cornelia M and Vergnaud, Anne-Claire and Verwoert, Germaine C and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and Vuckovic, Dragana and Watkins, Hugh and Wild, Sarah H and Willemsen, Gonneke and Wilson, James F and Wright, Alan F and Yao, Jie and Zemunik, Tatijana and Zhang, Weihua and Attia, John R and Butterworth, Adam S and Chasman, Daniel I and Conen, David and Cucca, Francesco and Danesh, John and Hayward, Caroline and Howson, Joanna M M and Laakso, Markku and Lakatta, Edward G and Langenberg, Claudia and Melander, Olle and Mook-Kanamori, Dennis O and Palmer, Colin N A and Risch, Lorenz and Scott, Robert A and Scott, Rodney J and Sever, Peter and Spector, Tim D and van der Harst, Pim and Wareham, Nicholas J and Zeggini, Eleftheria and Levy, Daniel and Munroe, Patricia B and Newton-Cheh, Christopher and Brown, Morris J and Metspalu, Andres and Hung, Adriana M and O{\textquoteright}Donnell, Christopher J and Edwards, Todd L and Psaty, Bruce M and Tzoulaki, Ioanna and Barnes, Michael R and Wain, Louise V and Elliott, Paul and Caulfield, Mark J} } @article {7920, title = {Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 Nov 01}, pages = {691-706}, abstract = {

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5~{\texttimes} 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0\% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.09.009}, author = {Ligthart, Symen and Vaez, Ahmad and V{\~o}sa, Urmo and Stathopoulou, Maria G and de Vries, Paul S and Prins, Bram P and van der Most, Peter J and Tanaka, Toshiko and Naderi, Elnaz and Rose, Lynda M and Wu, Ying and Karlsson, Robert and Barbalic, Maja and Lin, Honghuang and Pool, Rene and Zhu, Gu and Mace, Aurelien and Sidore, Carlo and Trompet, Stella and Mangino, Massimo and Sabater-Lleal, Maria and Kemp, John P and Abbasi, Ali and Kacprowski, Tim and Verweij, Niek and Smith, Albert V and Huang, Tao and Marzi, Carola and Feitosa, Mary F and Lohman, Kurt K and Kleber, Marcus E and Milaneschi, Yuri and Mueller, Christian and Huq, Mahmudul and Vlachopoulou, Efthymia and Lyytik{\"a}inen, Leo-Pekka and Oldmeadow, Christopher and Deelen, Joris and Perola, Markus and Zhao, Jing Hua and Feenstra, Bjarke and Amini, Marzyeh and Lahti, Jari and Schraut, Katharina E and Fornage, Myriam and Suktitipat, Bhoom and Chen, Wei-Min and Li, Xiaohui and Nutile, Teresa and Malerba, Giovanni and Luan, Jian{\textquoteright}an and Bak, Tom and Schork, Nicholas and del Greco M, Fabiola and Thiering, Elisabeth and Mahajan, Anubha and Marioni, Riccardo E and Mihailov, Evelin and Eriksson, Joel and Ozel, Ayse Bilge and Zhang, Weihua and Nethander, Maria and Cheng, Yu-Ching and Aslibekyan, Stella and Ang, Wei and Gandin, Ilaria and Yengo, Loic and Portas, Laura and Kooperberg, Charles and Hofer, Edith and Rajan, Kumar B and Schurmann, Claudia and den Hollander, Wouter and Ahluwalia, Tarunveer S and Zhao, Jing and Draisma, Harmen H M and Ford, Ian and Timpson, Nicholas and Teumer, Alexander and Huang, Hongyan and Wahl, Simone and Liu, Yongmei and Huang, Jie and Uh, Hae-Won and Geller, Frank and Joshi, Peter K and Yanek, Lisa R and Trabetti, Elisabetta and Lehne, Benjamin and Vozzi, Diego and Verbanck, Marie and Biino, Ginevra and Saba, Yasaman and Meulenbelt, Ingrid and O{\textquoteright}Connell, Jeff R and Laakso, Markku and Giulianini, Franco and Magnusson, Patrik K E and Ballantyne, Christie M and Hottenga, Jouke Jan and Montgomery, Grant W and Rivadineira, Fernando and Rueedi, Rico and Steri, Maristella and Herzig, Karl-Heinz and Stott, David J and Menni, Cristina and Fr{\r a}nberg, Mattias and St Pourcain, Beate and Felix, Stephan B and Pers, Tune H and Bakker, Stephan J L and Kraft, Peter and Peters, Annette and Vaidya, Dhananjay and Delgado, Graciela and Smit, Johannes H and Gro{\ss}mann, Vera and Sinisalo, Juha and Sepp{\"a}l{\"a}, Ilkka and Williams, Stephen R and Holliday, Elizabeth G and Moed, Matthijs and Langenberg, Claudia and R{\"a}ikk{\"o}nen, Katri and Ding, Jingzhong and Campbell, Harry and Sale, Mich{\`e}le M and Chen, Yii-der I and James, Alan L and Ruggiero, Daniela and Soranzo, Nicole and Hartman, Catharina A and Smith, Erin N and Berenson, Gerald S and Fuchsberger, Christian and Hernandez, Dena and Tiesler, Carla M T and Giedraitis, Vilmantas and Liewald, David and Fischer, Krista and Mellstr{\"o}m, Dan and Larsson, Anders and Wang, Yunmei and Scott, William R and Lorentzon, Matthias and Beilby, John and Ryan, Kathleen A and Pennell, Craig E and Vuckovic, Dragana and Balkau, Beverly and Concas, Maria Pina and Schmidt, Reinhold and Mendes de Leon, Carlos F and Bottinger, Erwin P and Kloppenburg, Margreet and Paternoster, Lavinia and Boehnke, Michael and Musk, A W and Willemsen, Gonneke and Evans, David M and Madden, Pamela A F and K{\"a}h{\"o}nen, Mika and Kutalik, Zolt{\'a}n and Zoledziewska, Magdalena and Karhunen, Ville and Kritchevsky, Stephen B and Sattar, Naveed and Lachance, Genevieve and Clarke, Robert and Harris, Tamara B and Raitakari, Olli T and Attia, John R and van Heemst, Diana and Kajantie, Eero and Sorice, Rossella and Gambaro, Giovanni and Scott, Robert A and Hicks, Andrew A and Ferrucci, Luigi and Standl, Marie and Lindgren, Cecilia M and Starr, John M and Karlsson, Magnus and Lind, Lars and Li, Jun Z and Chambers, John C and Mori, Trevor A and de Geus, Eco J C N and Heath, Andrew C and Martin, Nicholas G and Auvinen, Juha and Buckley, Brendan M and de Craen, Anton J M and Waldenberger, Melanie and Strauch, Konstantin and Meitinger, Thomas and Scott, Rodney J and McEvoy, Mark and Beekman, Marian and Bombieri, Cristina and Ridker, Paul M and Mohlke, Karen L and Pedersen, Nancy L and Morrison, Alanna C and Boomsma, Dorret I and Whitfield, John B and Strachan, David P and Hofman, Albert and Vollenweider, Peter and Cucca, Francesco and Jarvelin, Marjo-Riitta and Jukema, J Wouter and Spector, Tim D and Hamsten, Anders and Zeller, Tanja and Uitterlinden, Andr{\'e} G and Nauck, Matthias and Gudnason, Vilmundur and Qi, Lu and Grallert, Harald and Borecki, Ingrid B and Rotter, Jerome I and M{\"a}rz, Winfried and Wild, Philipp S and Lokki, Marja-Liisa and Boyle, Michael and Salomaa, Veikko and Melbye, Mads and Eriksson, Johan G and Wilson, James F and Penninx, Brenda W J H and Becker, Diane M and Worrall, Bradford B and Gibson, Greg and Krauss, Ronald M and Ciullo, Marina and Zaza, Gianluigi and Wareham, Nicholas J and Oldehinkel, Albertine J and Palmer, Lyle J and Murray, Sarah S and Pramstaller, Peter P and Bandinelli, Stefania and Heinrich, Joachim and Ingelsson, Erik and Deary, Ian J and M{\"a}gi, Reedik and Vandenput, Liesbeth and van der Harst, Pim and Desch, Karl C and Kooner, Jaspal S and Ohlsson, Claes and Hayward, Caroline and Lehtim{\"a}ki, Terho and Shuldiner, Alan R and Arnett, Donna K and Beilin, Lawrence J and Robino, Antonietta and Froguel, Philippe and Pirastu, Mario and Jess, Tine and Koenig, Wolfgang and Loos, Ruth J F and Evans, Denis A and Schmidt, Helena and Smith, George Davey and Slagboom, P Eline and Eiriksdottir, Gudny and Morris, Andrew P and Psaty, Bruce M and Tracy, Russell P and Nolte, Ilja M and Boerwinkle, Eric and Visvikis-Siest, Sophie and Reiner, Alex P and Gross, Myron and Bis, Joshua C and Franke, Lude and Franco, Oscar H and Benjamin, Emelia J and Chasman, Daniel I and Dupuis, Jos{\'e}e and Snieder, Harold and Dehghan, Abbas and Alizadeh, Behrooz Z} } @article {7924, title = {Genome-Wide Association Trans-Ethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.}, journal = {Circulation}, year = {2018}, month = {2018 Nov 20}, abstract = {

BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.

METHODS: We meta-analyzed genome-wide association results from 46,354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated approximately 35 million imputed variants with natural-log transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization (MR) analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.

RESULTS: We identified 13 novel genome-wide significant (p<=2.5x10) associations; 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. MR suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.

CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.118.034532}, author = {Sabater-Lleal, Maria and Huffman, Jennifer E and de Vries, Paul S and Marten, Jonathan and Mastrangelo, Michael A and Song, Ci and Pankratz, Nathan and Ward-Caviness, Cavin K and Yanek, Lisa R and Trompet, Stella and Delgado, Graciela E and Guo, Xiuqing and Bartz, Traci M and Martinez-Perez, Angel and Germain, Marine and de Haan, Hugoline G and Ozel, Ayse B and Polasek, Ozren and Smith, Albert V and Eicher, John D and Reiner, Alex P and Tang, Weihong and Davies, Neil M and Stott, David J and Rotter, Jerome I and Tofler, Geoffrey H and Boerwinkle, Eric and de Maat, Moniek P M and Kleber, Marcus E and Welsh, Paul and Brody, Jennifer A and Chen, Ming-Huei and Vaidya, Dhananjay and Soria, Jos{\'e} Manuel and Suchon, Pierre and van Hylckama Vlieg, Astrid and Desch, Karl C and Kolcic, Ivana and Joshi, Peter K and Launer, Lenore J and Harris, Tamara B and Campbell, Harry and Rudan, Igor and Becker, Diane M and Li, Jun Z and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Hofman, Albert and Franco, Oscar H and Cushman, Mary and Psaty, Bruce M and Morange, Pierre-Emmanuel and McKnight, Barbara and Chong, Michael R and Fernandez-Cadenas, Israel and Rosand, Jonathan and Lindgren, Arne and Gudnason, Vilmundur and Wilson, James F and Hayward, Caroline and Ginsburg, David and Fornage, Myriam and Rosendaal, Frits R and Souto, Juan Carlos and Becker, Lewis C and Jenny, Nancy S and M{\"a}rz, Winfried and Jukema, J Wouter and Dehghan, Abbas and Tr{\'e}gou{\"e}t, David-Alexandre and Morrison, Alanna C and Johnson, Andrew D and O{\textquoteright}Donnell, Christopher J and Strachan, David P and Lowenstein, Charles J and Smith, Nicholas L} } @article {7913, title = {GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 12 03}, pages = {5141}, abstract = {

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

}, keywords = {ADAMTS9 Protein, Amino Acid Oxidoreductases, Carotid Intima-Media Thickness, Coronary Disease, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Lod Score, Plaque, Atherosclerotic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-018-07340-5}, author = {Franceschini, Nora and Giambartolomei, Claudia and de Vries, Paul S and Finan, Chris and Bis, Joshua C and Huntley, Rachael P and Lovering, Ruth C and Tajuddin, Salman M and Winkler, Thomas W and Graff, Misa and Kavousi, Maryam and Dale, Caroline and Smith, Albert V and Hofer, Edith and van Leeuwen, Elisabeth M and Nolte, Ilja M and Lu, Lingyi and Scholz, Markus and Sargurupremraj, Muralidharan and Pitk{\"a}nen, Niina and Franz{\'e}n, Oscar and Joshi, Peter K and Noordam, Raymond and Marioni, Riccardo E and Hwang, Shih-Jen and Musani, Solomon K and Schminke, Ulf and Palmas, Walter and Isaacs, Aaron and Correa, Adolfo and Zonderman, Alan B and Hofman, Albert and Teumer, Alexander and Cox, Amanda J and Uitterlinden, Andr{\'e} G and Wong, Andrew and Smit, Andries J and Newman, Anne B and Britton, Annie and Ruusalepp, Arno and Sennblad, Bengt and Hedblad, Bo and Pasaniuc, Bogdan and Penninx, Brenda W and Langefeld, Carl D and Wassel, Christina L and Tzourio, Christophe and Fava, Cristiano and Baldassarre, Damiano and O{\textquoteright}Leary, Daniel H and Teupser, Daniel and Kuh, Diana and Tremoli, Elena and Mannarino, Elmo and Grossi, Enzo and Boerwinkle, Eric and Schadt, Eric E and Ingelsson, Erik and Veglia, Fabrizio and Rivadeneira, Fernando and Beutner, Frank and Chauhan, Ganesh and Heiss, Gerardo and Snieder, Harold and Campbell, Harry and V{\"o}lzke, Henry and Markus, Hugh S and Deary, Ian J and Jukema, J Wouter and de Graaf, Jacqueline and Price, Jacqueline and Pott, Janne and Hopewell, Jemma C and Liang, Jingjing and Thiery, Joachim and Engmann, Jorgen and Gertow, Karl and Rice, Kenneth and Taylor, Kent D and Dhana, Klodian and Kiemeney, Lambertus A L M and Lind, Lars and Raffield, Laura M and Launer, Lenore J and Holdt, Lesca M and D{\"o}rr, Marcus and Dichgans, Martin and Traylor, Matthew and Sitzer, Matthias and Kumari, Meena and Kivimaki, Mika and Nalls, Mike A and Melander, Olle and Raitakari, Olli and Franco, Oscar H and Rueda-Ochoa, Oscar L and Roussos, Panos and Whincup, Peter H and Amouyel, Philippe and Giral, Philippe and Anugu, Pramod and Wong, Quenna and Malik, Rainer and Rauramaa, Rainer and Burkhardt, Ralph and Hardy, Rebecca and Schmidt, Reinhold and de Mutsert, Ren{\'e}e and Morris, Richard W and Strawbridge, Rona J and Wannamethee, S Goya and H{\"a}gg, Sara and Shah, Sonia and McLachlan, Stela and Trompet, Stella and Seshadri, Sudha and Kurl, Sudhir and Heckbert, Susan R and Ring, Susan and Harris, Tamara B and Lehtim{\"a}ki, Terho and Galesloot, Tessel E and Shah, Tina and de Faire, Ulf and Plagnol, Vincent and Rosamond, Wayne D and Post, Wendy and Zhu, Xiaofeng and Zhang, Xiaoling and Guo, Xiuqing and Saba, Yasaman and Dehghan, Abbas and Seldenrijk, Adrie and Morrison, Alanna C and Hamsten, Anders and Psaty, Bruce M and van Duijn, Cornelia M and Lawlor, Deborah A and Mook-Kanamori, Dennis O and Bowden, Donald W and Schmidt, Helena and Wilson, James F and Wilson, James G and Rotter, Jerome I and Wardlaw, Joanna M and Deanfield, John and Halcox, Julian and Lyytik{\"a}inen, Leo-Pekka and Loeffler, Markus and Evans, Michele K and Debette, Stephanie and Humphries, Steve E and V{\"o}lker, Uwe and Gudnason, Vilmundur and Hingorani, Aroon D and Bj{\"o}rkegren, Johan L M and Casas, Juan P and O{\textquoteright}Donnell, Christopher J} } @article {8206, title = {Genetic architecture of subcortical brain structures in 38,851 individuals.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Nov}, pages = {1624-1636}, abstract = {

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

}, issn = {1546-1718}, doi = {10.1038/s41588-019-0511-y}, author = {Satizabal, Claudia L and Adams, Hieab H H and Hibar, Derrek P and White, Charles C and Knol, Maria J and Stein, Jason L and Scholz, Markus and Sargurupremraj, Muralidharan and Jahanshad, Neda and Roshchupkin, Gennady V and Smith, Albert V and Bis, Joshua C and Jian, Xueqiu and Luciano, Michelle and Hofer, Edith and Teumer, Alexander and van der Lee, Sven J and Yang, Jingyun and Yanek, Lisa R and Lee, Tom V and Li, Shuo and Hu, Yanhui and Koh, Jia Yu and Eicher, John D and Desrivi{\`e}res, Sylvane and Arias-Vasquez, Alejandro and Chauhan, Ganesh and Athanasiu, Lavinia and Renter{\'\i}a, Miguel E and Kim, Sungeun and Hoehn, David and Armstrong, Nicola J and Chen, Qiang and Holmes, Avram J and den Braber, Anouk and Kloszewska, Iwona and Andersson, Micael and Espeseth, Thomas and Grimm, Oliver and Abramovic, Lucija and Alhusaini, Saud and Milaneschi, Yuri and Papmeyer, Martina and Axelsson, Tomas and Ehrlich, Stefan and Roiz-Santia{\~n}ez, Roberto and Kraemer, Bernd and H{\r a}berg, Asta K and Jones, Hannah J and Pike, G Bruce and Stein, Dan J and Stevens, Allison and Bralten, Janita and Vernooij, Meike W and Harris, Tamara B and Filippi, Irina and Witte, A Veronica and Guadalupe, Tulio and Wittfeld, Katharina and Mosley, Thomas H and Becker, James T and Doan, Nhat Trung and Hagenaars, Saskia P and Saba, Yasaman and Cuellar-Partida, Gabriel and Amin, Najaf and Hilal, Saima and Nho, Kwangsik and Mirza-Schreiber, Nazanin and Arfanakis, Konstantinos and Becker, Diane M and Ames, David and Goldman, Aaron L and Lee, Phil H and Boomsma, Dorret I and Lovestone, Simon and Giddaluru, Sudheer and Le Hellard, Stephanie and Mattheisen, Manuel and Bohlken, Marc M and Kasperaviciute, Dalia and Schmaal, Lianne and Lawrie, Stephen M and Agartz, Ingrid and Walton, Esther and Tordesillas-Gutierrez, Diana and Davies, Gareth E and Shin, Jean and Ipser, Jonathan C and Vinke, Louis N and Hoogman, Martine and Jia, Tianye and Burkhardt, Ralph and Klein, Marieke and Crivello, Fabrice and Janowitz, Deborah and Carmichael, Owen and Haukvik, Unn K and Aribisala, Benjamin S and Schmidt, Helena and Strike, Lachlan T and Cheng, Ching-Yu and Risacher, Shannon L and P{\"u}tz, Benno and Fleischman, Debra A and Assareh, Amelia A and Mattay, Venkata S and Buckner, Randy L and Mecocci, Patrizia and Dale, Anders M and Cichon, Sven and Boks, Marco P and Matarin, Mar and Penninx, Brenda W J H and Calhoun, Vince D and Chakravarty, M Mallar and Marquand, Andre F and Macare, Christine and Kharabian Masouleh, Shahrzad and Oosterlaan, Jaap and Amouyel, Philippe and Hegenscheid, Katrin and Rotter, Jerome I and Schork, Andrew J and Liewald, David C M and de Zubicaray, Greig I and Wong, Tien Yin and Shen, Li and S{\"a}mann, Philipp G and Brodaty, Henry and Roffman, Joshua L and de Geus, Eco J C and Tsolaki, Magda and Erk, Susanne and van Eijk, Kristel R and Cavalleri, Gianpiero L and van der Wee, Nic J A and McIntosh, Andrew M and Gollub, Randy L and Bulayeva, Kazima B and Bernard, Manon and Richards, Jennifer S and Himali, Jayandra J and Loeffler, Markus and Rommelse, Nanda and Hoffmann, Wolfgang and Westlye, Lars T and Vald{\'e}s Hern{\'a}ndez, Maria C and Hansell, Narelle K and van Erp, Theo G M and Wolf, Christiane and Kwok, John B J and Vellas, Bruno and Heinz, Andreas and Olde Loohuis, Loes M and Delanty, Norman and Ho, Beng-Choon and Ching, Christopher R K and Shumskaya, Elena and Singh, Baljeet and Hofman, Albert and van der Meer, Dennis and Homuth, Georg and Psaty, Bruce M and Bastin, Mark E and Montgomery, Grant W and Foroud, Tatiana M and Reppermund, Simone and Hottenga, Jouke-Jan and Simmons, Andrew and Meyer-Lindenberg, Andreas and Cahn, Wiepke and Whelan, Christopher D and van Donkelaar, Marjolein M J and Yang, Qiong and Hosten, Norbert and Green, Robert C and Thalamuthu, Anbupalam and Mohnke, Sebastian and Hulshoff Pol, Hilleke E and Lin, Honghuang and Jack, Clifford R and Schofield, Peter R and M{\"u}hleisen, Thomas W and Maillard, Pauline and Potkin, Steven G and Wen, Wei and Fletcher, Evan and Toga, Arthur W and Gruber, Oliver and Huentelman, Matthew and Davey Smith, George and Launer, Lenore J and Nyberg, Lars and J{\"o}nsson, Erik G and Crespo-Facorro, Benedicto and Koen, Nastassja and Greve, Douglas N and Uitterlinden, Andr{\'e} G and Weinberger, Daniel R and Steen, Vidar M and Fedko, Iryna O and Groenewold, Nynke A and Niessen, Wiro J and Toro, Roberto and Tzourio, Christophe and Longstreth, William T and Ikram, M Kamran and Smoller, Jordan W and van Tol, Marie-Jose and Sussmann, Jessika E and Paus, Tom{\'a}{\v s} and Lema{\^\i}tre, Herv{\'e} and Schroeter, Matthias L and Mazoyer, Bernard and Andreassen, Ole A and Holsboer, Florian and Depondt, Chantal and Veltman, Dick J and Turner, Jessica A and Pausova, Zdenka and Schumann, Gunter and van Rooij, Daan and Djurovic, Srdjan and Deary, Ian J and McMahon, Katie L and M{\"u}ller-Myhsok, Bertram and Brouwer, Rachel M and Soininen, Hilkka and Pandolfo, Massimo and Wassink, Thomas H and Cheung, Joshua W and Wolfers, Thomas and Martinot, Jean-Luc and Zwiers, Marcel P and Nauck, Matthias and Melle, Ingrid and Martin, Nicholas G and Kanai, Ryota and Westman, Eric and Kahn, Ren{\'e} S and Sisodiya, Sanjay M and White, Tonya and Saremi, Arvin and van Bokhoven, Hans and Brunner, Han G and V{\"o}lzke, Henry and Wright, Margaret J and van {\textquoteright}t Ent, Dennis and N{\"o}then, Markus M and Ophoff, Roel A and Buitelaar, Jan K and Fern{\'a}ndez, Guill{\'e}n and Sachdev, Perminder S and Rietschel, Marcella and van Haren, Neeltje E M and Fisher, Simon E and Beiser, Alexa S and Francks, Clyde and Saykin, Andrew J and Mather, Karen A and Romanczuk-Seiferth, Nina and Hartman, Catharina A and DeStefano, Anita L and Heslenfeld, Dirk J and Weiner, Michael W and Walter, Henrik and Hoekstra, Pieter J and Nyquist, Paul A and Franke, Barbara and Bennett, David A and Grabe, Hans J and Johnson, Andrew D and Chen, Christopher and van Duijn, Cornelia M and Lopez, Oscar L and Fornage, Myriam and Wardlaw, Joanna M and Schmidt, Reinhold and DeCarli, Charles and De Jager, Philip L and Villringer, Arno and Debette, Stephanie and Gudnason, Vilmundur and Medland, Sarah E and Shulman, Joshua M and Thompson, Paul M and Seshadri, Sudha and Ikram, M Arfan} } @article {7977, title = {Genetic meta-analysis of diagnosed Alzheimer{\textquoteright}s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Mar}, pages = {414-430}, abstract = {

Risk for late-onset Alzheimer{\textquoteright}s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer{\textquoteright}s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer{\textquoteright}s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 {\texttimes} 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

}, issn = {1546-1718}, doi = {10.1038/s41588-019-0358-2}, author = {Kunkle, Brian W and Grenier-Boley, Benjamin and Sims, Rebecca and Bis, Joshua C and Damotte, Vincent and Naj, Adam C and Boland, Anne and Vronskaya, Maria and van der Lee, Sven J and Amlie-Wolf, Alexandre and Bellenguez, C{\'e}line and Frizatti, Aura and Chouraki, Vincent and Martin, Eden R and Sleegers, Kristel and Badarinarayan, Nandini and Jakobsdottir, Johanna and Hamilton-Nelson, Kara L and Moreno-Grau, Sonia and Olaso, Robert and Raybould, Rachel and Chen, Yuning and Kuzma, Amanda B and Hiltunen, Mikko and Morgan, Taniesha and Ahmad, Shahzad and Vardarajan, Badri N and Epelbaum, Jacques and Hoffmann, Per and Boada, Merce and Beecham, Gary W and Garnier, Jean-Guillaume and Harold, Denise and Fitzpatrick, Annette L and Valladares, Otto and Moutet, Marie-Laure and Gerrish, Amy and Smith, Albert V and Qu, Liming and Bacq, Delphine and Denning, Nicola and Jian, Xueqiu and Zhao, Yi and Del Zompo, Maria and Fox, Nick C and Choi, Seung-Hoan and Mateo, Ignacio and Hughes, Joseph T and Adams, Hieab H and Malamon, John and Sanchez-Garcia, Florentino and Patel, Yogen and Brody, Jennifer A and Dombroski, Beth A and Naranjo, Maria Candida Deniz and Daniilidou, Makrina and Eiriksdottir, Gudny and Mukherjee, Shubhabrata and Wallon, David and Uphill, James and Aspelund, Thor and Cantwell, Laura B and Garzia, Fabienne and Galimberti, Daniela and Hofer, Edith and Butkiewicz, Mariusz and Fin, Bertrand and Scarpini, Elio and Sarnowski, Chloe and Bush, Will S and Meslage, St{\'e}phane and Kornhuber, Johannes and White, Charles C and Song, Yuenjoo and Barber, Robert C and Engelborghs, Sebastiaan and Sordon, Sabrina and Voijnovic, Dina and Adams, Perrie M and Vandenberghe, Rik and Mayhaus, Manuel and Cupples, L Adrienne and Albert, Marilyn S and De Deyn, Peter P and Gu, Wei and Himali, Jayanadra J and Beekly, Duane and Squassina, Alessio and Hartmann, Annette M and Orellana, Adelina and Blacker, Deborah and Rodriguez-Rodriguez, Eloy and Lovestone, Simon and Garcia, Melissa E and Doody, Rachelle S and Munoz-Fernadez, Carmen and Sussams, Rebecca and Lin, Honghuang and Fairchild, Thomas J and Benito, Yolanda A and Holmes, Clive and Karamuji{\'c}-{\v C}omi{\'c}, Hata and Frosch, Matthew P and Thonberg, H{\r a}kan and Maier, Wolfgang and Roschupkin, Gena and Ghetti, Bernardino and Giedraitis, Vilmantas and Kawalia, Amit and Li, Shuo and Huebinger, Ryan M and Kilander, Lena and Moebus, Susanne and Hernandez, Isabel and Kamboh, M Ilyas and Brundin, RoseMarie and Turton, James and Yang, Qiong and Katz, Mindy J and Concari, Letizia and Lord, Jenny and Beiser, Alexa S and Keene, C Dirk and Helisalmi, Seppo and Kloszewska, Iwona and Kukull, Walter A and Koivisto, Anne Maria and Lynch, Aoibhinn and Tarraga, Lluis and Larson, Eric B and Haapasalo, Annakaisa and Lawlor, Brian and Mosley, Thomas H and Lipton, Richard B and Solfrizzi, Vincenzo and Gill, Michael and Longstreth, W T and Montine, Thomas J and Frisardi, Vincenza and Diez-Fairen, Monica and Rivadeneira, Fernando and Petersen, Ronald C and Deramecourt, Vincent and Alvarez, Ignacio and Salani, Francesca and Ciaramella, Antonio and Boerwinkle, Eric and Reiman, Eric M and Fi{\'e}vet, Nathalie and Rotter, Jerome I and Reisch, Joan S and Hanon, Olivier and Cupidi, Chiara and Andre Uitterlinden, A G and Royall, Donald R and Dufouil, Carole and Maletta, Raffaele Giovanni and de Rojas, Itziar and Sano, Mary and Brice, Alexis and Cecchetti, Roberta and George-Hyslop, Peter St and Ritchie, Karen and Tsolaki, Magda and Tsuang, Debby W and Dubois, Bruno and Craig, David and Wu, Chuang-Kuo and Soininen, Hilkka and Avramidou, Despoina and Albin, Roger L and Fratiglioni, Laura and Germanou, Antonia and Apostolova, Liana G and Keller, Lina and Koutroumani, Maria and Arnold, Steven E and Panza, Francesco and Gkatzima, Olymbia and Asthana, Sanjay and Hannequin, Didier and Whitehead, Patrice and Atwood, Craig S and Caffarra, Paolo and Hampel, Harald and Quintela, In{\'e}s and Carracedo, Angel and Lannfelt, Lars and Rubinsztein, David C and Barnes, Lisa L and Pasquier, Florence and Fr{\"o}lich, Lutz and Barral, Sandra and McGuinness, Bernadette and Beach, Thomas G and Johnston, Janet A and Becker, James T and Passmore, Peter and Bigio, Eileen H and Schott, Jonathan M and Bird, Thomas D and Warren, Jason D and Boeve, Bradley F and Lupton, Michelle K and Bowen, James D and Proitsi, Petra and Boxer, Adam and Powell, John F and Burke, James R and Kauwe, John S K and Burns, Jeffrey M and Mancuso, Michelangelo and Buxbaum, Joseph D and Bonuccelli, Ubaldo and Cairns, Nigel J and McQuillin, Andrew and Cao, Chuanhai and Livingston, Gill and Carlson, Chris S and Bass, Nicholas J and Carlsson, Cynthia M and Hardy, John and Carney, Regina M and Bras, Jose and Carrasquillo, Minerva M and Guerreiro, Rita and Allen, Mariet and Chui, Helena C and Fisher, Elizabeth and Masullo, Carlo and Crocco, Elizabeth A and DeCarli, Charles and Bisceglio, Gina and Dick, Malcolm and Ma, Li and Duara, Ranjan and Graff-Radford, Neill R and Evans, Denis A and Hodges, Angela and Faber, Kelley M and Scherer, Martin and Fallon, Kenneth B and Riemenschneider, Matthias and Fardo, David W and Heun, Reinhard and Farlow, Martin R and K{\"o}lsch, Heike and Ferris, Steven and Leber, Markus and Foroud, Tatiana M and Heuser, Isabella and Galasko, Douglas R and Giegling, Ina and Gearing, Marla and H{\"u}ll, Michael and Geschwind, Daniel H and Gilbert, John R and Morris, John and Green, Robert C and Mayo, Kevin and Growdon, John H and Feulner, Thomas and Hamilton, Ronald L and Harrell, Lindy E and Drichel, Dmitriy and Honig, Lawrence S and Cushion, Thomas D and Huentelman, Matthew J and Hollingworth, Paul and Hulette, Christine M and Hyman, Bradley T and Marshall, Rachel and Jarvik, Gail P and Meggy, Alun and Abner, Erin and Menzies, Georgina E and Jin, Lee-Way and Leonenko, Ganna and Real, Luis M and Jun, Gyungah R and Baldwin, Clinton T and Grozeva, Detelina and Karydas, Anna and Russo, Giancarlo and Kaye, Jeffrey A and Kim, Ronald and Jessen, Frank and Kowall, Neil W and Vellas, Bruno and Kramer, Joel H and Vardy, Emma and LaFerla, Frank M and J{\"o}ckel, Karl-Heinz and Lah, James J and Dichgans, Martin and Leverenz, James B and Mann, David and Levey, Allan I and Pickering-Brown, Stuart and Lieberman, Andrew P and Klopp, Norman and Lunetta, Kathryn L and Wichmann, H-Erich and Lyketsos, Constantine G and Morgan, Kevin and Marson, Daniel C and Brown, Kristelle and Martiniuk, Frank and Medway, Christopher and Mash, Deborah C and N{\"o}then, Markus M and Masliah, Eliezer and Hooper, Nigel M and McCormick, Wayne C and Daniele, Antonio and McCurry, Susan M and Bayer, Anthony and McDavid, Andrew N and Gallacher, John and McKee, Ann C and van den Bussche, Hendrik and Mesulam, Marsel and Brayne, Carol and Miller, Bruce L and Riedel-Heller, Steffi and Miller, Carol A and Miller, Joshua W and Al-Chalabi, Ammar and Morris, John C and Shaw, Christopher E and Myers, Amanda J and Wiltfang, Jens and O{\textquoteright}Bryant, Sid and Olichney, John M and Alvarez, Victoria and Parisi, Joseph E and Singleton, Andrew B and Paulson, Henry L and Collinge, John and Perry, William R and Mead, Simon and Peskind, Elaine and Cribbs, David H and Rossor, Martin and Pierce, Aimee and Ryan, Natalie S and Poon, Wayne W and Nacmias, Benedetta and Potter, Huntington and Sorbi, Sandro and Quinn, Joseph F and Sacchinelli, Eleonora and Raj, Ashok and Spalletta, Gianfranco and Raskind, Murray and Caltagirone, Carlo and Boss{\`u}, Paola and Orfei, Maria Donata and Reisberg, Barry and Clarke, Robert and Reitz, Christiane and Smith, A David and Ringman, John M and Warden, Donald and Roberson, Erik D and Wilcock, Gordon and Rogaeva, Ekaterina and Bruni, Amalia Cecilia and Rosen, Howard J and Gallo, Maura and Rosenberg, Roger N and Ben-Shlomo, Yoav and Sager, Mark A and Mecocci, Patrizia and Saykin, Andrew J and Pastor, Pau and Cuccaro, Michael L and Vance, Jeffery M and Schneider, Julie A and Schneider, Lori S and Slifer, Susan and Seeley, William W and Smith, Amanda G and Sonnen, Joshua A and Spina, Salvatore and Stern, Robert A and Swerdlow, Russell H and Tang, Mitchell and Tanzi, Rudolph E and Trojanowski, John Q and Troncoso, Juan C and Van Deerlin, Vivianna M and Van Eldik, Linda J and Vinters, Harry V and Vonsattel, Jean Paul and Weintraub, Sandra and Welsh-Bohmer, Kathleen A and Wilhelmsen, Kirk C and Williamson, Jennifer and Wingo, Thomas S and Woltjer, Randall L and Wright, Clinton B and Yu, Chang-En and Yu, Lei and Saba, Yasaman and Pilotto, Alberto and Bullido, Mar{\'\i}a J and Peters, Oliver and Crane, Paul K and Bennett, David and Bosco, Paola and Coto, Eliecer and Boccardi, Virginia and De Jager, Phil L and Lleo, Alberto and Warner, Nick and Lopez, Oscar L and Ingelsson, Martin and Deloukas, Panagiotis and Cruchaga, Carlos and Graff, Caroline and Gwilliam, Rhian and Fornage, Myriam and Goate, Alison M and S{\'a}nchez-Juan, Pascual and Kehoe, Patrick G and Amin, Najaf and Ertekin-Taner, Nilifur and Berr, Claudine and Debette, Stephanie and Love, Seth and Launer, Lenore J and Younkin, Steven G and Dartigues, Jean-Fran{\c c}ois and Corcoran, Chris and Ikram, M Arfan and Dickson, Dennis W and Nicolas, Ga{\"e}l and Campion, Dominique and Tschanz, JoAnn and Schmidt, Helena and Hakonarson, Hakon and Clarimon, Jordi and Munger, Ron and Schmidt, Reinhold and Farrer, Lindsay A and Van Broeckhoven, Christine and C O{\textquoteright}Donovan, Michael and DeStefano, Anita L and Jones, Lesley and Haines, Jonathan L and Deleuze, Jean-Francois and Owen, Michael J and Gudnason, Vilmundur and Mayeux, Richard and Escott-Price, Valentina and Psaty, Bruce M and Ramirez, Alfredo and Wang, Li-San and Ruiz, Agustin and van Duijn, Cornelia M and Holmans, Peter A and Seshadri, Sudha and Williams, Julie and Amouyel, Phillippe and Schellenberg, Gerard D and Lambert, Jean-Charles and Pericak-Vance, Margaret A} } @article {8381, title = {Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.}, journal = {Mol Psychiatry}, year = {2020}, month = {2020 May 05}, abstract = {

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 {\texttimes} 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

}, issn = {1476-5578}, doi = {10.1038/s41380-020-0719-3}, author = {de Las Fuentes, Lisa and Sung, Yun Ju and Noordam, Raymond and Winkler, Thomas and Feitosa, Mary F and Schwander, Karen and Bentley, Amy R and Brown, Michael R and Guo, Xiuqing and Manning, Alisa and Chasman, Daniel I and Aschard, Hugues and Bartz, Traci M and Bielak, Lawrence F and Campbell, Archie and Cheng, Ching-Yu and Dorajoo, Rajkumar and Hartwig, Fernando P and Horimoto, A R V R and Li, Changwei and Li-Gao, Ruifang and Liu, Yongmei and Marten, Jonathan and Musani, Solomon K and Ntalla, Ioanna and Rankinen, Tuomo and Richard, Melissa and Sim, Xueling and Smith, Albert V and Tajuddin, Salman M and Tayo, Bamidele O and Vojinovic, Dina and Warren, Helen R and Xuan, Deng and Alver, Maris and Boissel, Mathilde and Chai, Jin-Fang and Chen, Xu and Christensen, Kaare and Divers, Jasmin and Evangelou, Evangelos and Gao, Chuan and Girotto, Giorgia and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Kuhnel, Brigitte and Laguzzi, Federica and Li, Xiaoyin and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Poveda, Alaitz and Rauramaa, Rainer and Riaz, Muhammad and Rueedi, Rico and Shu, Xiao-Ou and Snieder, Harold and Sofer, Tamar and Takeuchi, Fumihiko and Verweij, Niek and Ware, Erin B and Weiss, Stefan and Yanek, Lisa R and Amin, Najaf and Arking, Dan E and Arnett, Donna K and Bergmann, Sven and Boerwinkle, Eric and Brody, Jennifer A and Broeckel, Ulrich and Brumat, Marco and Burke, Gregory and Cabrera, Claudia P and Canouil, Micka{\"e}l and Chee, Miao Li and Chen, Yii-Der Ida and Cocca, Massimiliano and Connell, John and de Silva, H Janaka and de Vries, Paul S and Eiriksdottir, Gudny and Faul, Jessica D and Fisher, Virginia and Forrester, Terrence and Fox, Ervin F and Friedlander, Yechiel and Gao, He and Gigante, Bruna and Giulianini, Franco and Gu, Chi Charles and Gu, Dongfeng and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hunt, Steven and Ikram, M Arfan and Irvin, Marguerite R and K{\"a}h{\"o}nen, Mika and Kavousi, Maryam and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Komulainen, Pirjo and Kraja, Aldi T and Krieger, J E and Langefeld, Carl D and Li, Yize and Liang, Jingjing and Liewald, David C M and Liu, Ching-Ti and Liu, Jianjun and Lohman, Kurt K and M{\"a}gi, Reedik and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mook-Kanamori, Dennis O and Nalls, Mike A and Nelson, Christopher P and Norris, Jill M and O{\textquoteright}Connell, Jeff and Ogunniyi, Adesola and Padmanabhan, Sandosh and Palmer, Nicholette D and Pedersen, Nancy L and Perls, Thomas and Peters, Annette and Petersmann, Astrid and Peyser, Patricia A and Polasek, Ozren and Porteous, David J and Raffel, Leslie J and Rice, Treva K and Rotter, Jerome I and Rudan, Igor and Rueda-Ochoa, Oscar-Leonel and Sabanayagam, Charumathi and Salako, Babatunde L and Schreiner, Pamela J and Shikany, James M and Sidney, Stephen S and Sims, Mario and Sitlani, Colleen M and Smith, Jennifer A and Starr, John M and Strauch, Konstantin and Swertz, Morris A and Teumer, Alexander and Tham, Yih Chung and Uitterlinden, Andr{\'e} G and Vaidya, Dhananjay and van der Ende, M Yldau and Waldenberger, Melanie and Wang, Lihua and Wang, Ya-Xing and Wei, Wen-Bin and Weir, David R and Wen, Wanqing and Yao, Jie and Yu, Bing and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Bowden, Donald W and Deary, Ian J and D{\"o}rr, Marcus and Esko, T{\~o}nu and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Jonas, Jost Bruno and Kammerer, Candace M and Kato, Norihiro and Lakka, Timo A and Leander, Karin and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Marques-Vidal, Pedro and Penninx, Brenda W J H and Samani, Nilesh J and van der Harst, Pim and Wagenknecht, Lynne E and Wu, Tangchun and Zheng, Wei and Zhu, Xiaofeng and Bouchard, Claude and Cooper, Richard S and Correa, Adolfo and Evans, Michele K and Gudnason, Vilmundur and Hayward, Caroline and Horta, Bernardo L and Kelly, Tanika N and Kritchevsky, Stephen B and Levy, Daniel and Palmas, Walter R and Pereira, A C and Province, Michael M and Psaty, Bruce M and Ridker, Paul M and Rotimi, Charles N and Tai, E Shyong and van Dam, Rob M and van Duijn, Cornelia M and Wong, Tien Yin and Rice, Kenneth and Gauderman, W James and Morrison, Alanna C and North, Kari E and Kardia, Sharon L R and Caulfield, Mark J and Elliott, Paul and Munroe, Patricia B and Franks, Paul W and Rao, Dabeeru C and Fornage, Myriam} } @article {8835, title = {Genetic insights into biological mechanisms governing human ovarian ageing.}, journal = {Nature}, volume = {596}, year = {2021}, month = {2021 Aug}, pages = {393-397}, abstract = {

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1\% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

}, issn = {1476-4687}, doi = {10.1038/s41586-021-03779-7}, author = {Ruth, Katherine S and Day, Felix R and Hussain, Jazib and Mart{\'\i}nez-Marchal, Ana and Aiken, Catherine E and Azad, Ajuna and Thompson, Deborah J and Knoblochova, Lucie and Abe, Hironori and Tarry-Adkins, Jane L and Gonzalez, Javier Martin and Fontanillas, Pierre and Claringbould, Annique and Bakker, Olivier B and Sulem, Patrick and Walters, Robin G and Terao, Chikashi and Turon, Sandra and Horikoshi, Momoko and Lin, Kuang and Onland-Moret, N Charlotte and Sankar, Aditya and Hertz, Emil Peter Thrane and Timshel, Pascal N and Shukla, Vallari and Borup, Rehannah and Olsen, Kristina W and Aguilera, Paula and Ferrer-Roda, M{\`o}nica and Huang, Yan and Stankovic, Stasa and Timmers, Paul R H J and Ahearn, Thomas U and Alizadeh, Behrooz Z and Naderi, Elnaz and Andrulis, Irene L and Arnold, Alice M and Aronson, Kristan J and Augustinsson, Annelie and Bandinelli, Stefania and Barbieri, Caterina M and Beaumont, Robin N and Becher, Heiko and Beckmann, Matthias W and Benonisdottir, Stefania and Bergmann, Sven and Bochud, Murielle and Boerwinkle, Eric and Bojesen, Stig E and Bolla, Manjeet K and Boomsma, Dorret I and Bowker, Nicholas and Brody, Jennifer A and Broer, Linda and Buring, Julie E and Campbell, Archie and Campbell, Harry and Castelao, Jose E and Catamo, Eulalia and Chanock, Stephen J and Chenevix-Trench, Georgia and Ciullo, Marina and Corre, Tanguy and Couch, Fergus J and Cox, Angela and Crisponi, Laura and Cross, Simon S and Cucca, Francesco and Czene, Kamila and Smith, George Davey and de Geus, Eco J C N and de Mutsert, Ren{\'e}e and De Vivo, Immaculata and Demerath, Ellen W and Dennis, Joe and Dunning, Alison M and Dwek, Miriam and Eriksson, Mikael and Esko, T{\~o}nu and Fasching, Peter A and Faul, Jessica D and Ferrucci, Luigi and Franceschini, Nora and Frayling, Timothy M and Gago-Dominguez, Manuela and Mezzavilla, Massimo and Garc{\'\i}a-Closas, Montserrat and Gieger, Christian and Giles, Graham G and Grallert, Harald and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Gu{\'e}nel, Pascal and Haiman, Christopher A and H{\r a}kansson, Niclas and Hall, Per and Hayward, Caroline and He, Chunyan and He, Wei and Heiss, Gerardo and H{\o}ffding, Miya K and Hopper, John L and Hottenga, Jouke J and Hu, Frank and Hunter, David and Ikram, Mohammad A and Jackson, Rebecca D and Joaquim, Micaella D R and John, Esther M and Joshi, Peter K and Karasik, David and Kardia, Sharon L R and Kartsonaki, Christiana and Karlsson, Robert and Kitahara, Cari M and Kolcic, Ivana and Kooperberg, Charles and Kraft, Peter and Kurian, Allison W and Kutalik, Zolt{\'a}n and La Bianca, Martina and Lachance, Genevieve and Langenberg, Claudia and Launer, Lenore J and Laven, Joop S E and Lawlor, Deborah A and Le Marchand, Lo{\"\i}c and Li, Jingmei and Lindblom, Annika and Lindstr{\"o}m, Sara and Lindstrom, Tricia and Linet, Martha and Liu, Yongmei and Liu, Simin and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Magnusson, Patrik K E and Mangino, Massimo and Mannermaa, Arto and Marco, Brumat and Marten, Jonathan and Martin, Nicholas G and Mbarek, Hamdi and McKnight, Barbara and Medland, Sarah E and Meisinger, Christa and Meitinger, Thomas and Menni, Cristina and Metspalu, Andres and Milani, Lili and Milne, Roger L and Montgomery, Grant W and Mook-Kanamori, Dennis O and Mulas, Antonella and Mulligan, Anna M and Murray, Alison and Nalls, Mike A and Newman, Anne and Noordam, Raymond and Nutile, Teresa and Nyholt, Dale R and Olshan, Andrew F and Olsson, H{\r a}kan and Painter, Jodie N and Patel, Alpa V and Pedersen, Nancy L and Perjakova, Natalia and Peters, Annette and Peters, Ulrike and Pharoah, Paul D P and Polasek, Ozren and Porcu, Eleonora and Psaty, Bruce M and Rahman, Iffat and Rennert, Gad and Rennert, Hedy S and Ridker, Paul M and Ring, Susan M and Robino, Antonietta and Rose, Lynda M and Rosendaal, Frits R and Rossouw, Jacques and Rudan, Igor and Rueedi, Rico and Ruggiero, Daniela and Sala, Cinzia F and Saloustros, Emmanouil and Sandler, Dale P and Sanna, Serena and Sawyer, Elinor J and Sarnowski, Chloe and Schlessinger, David and Schmidt, Marjanka K and Schoemaker, Minouk J and Schraut, Katharina E and Scott, Christopher and Shekari, Saleh and Shrikhande, Amruta and Smith, Albert V and Smith, Blair H and Smith, Jennifer A and Sorice, Rossella and Southey, Melissa C and Spector, Tim D and Spinelli, John J and Stampfer, Meir and St{\"o}ckl, Doris and van Meurs, Joyce B J and Strauch, Konstantin and Styrkarsdottir, Unnur and Swerdlow, Anthony J and Tanaka, Toshiko and Teras, Lauren R and Teumer, Alexander and {\TH}orsteinsdottir, Unnur and Timpson, Nicholas J and Toniolo, Daniela and Traglia, Michela and Troester, Melissa A and Truong, Th{\'e}r{\`e}se and Tyrrell, Jessica and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Vachon, Celine M and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and V{\"o}lzke, Henry and Wang, Qin and Wareham, Nicholas J and Weinberg, Clarice R and Weir, David R and Wilcox, Amber N and van Dijk, Ko Willems and Willemsen, Gonneke and Wilson, James F and Wolffenbuttel, Bruce H R and Wolk, Alicja and Wood, Andrew R and Zhao, Wei and Zygmunt, Marek and Chen, Zhengming and Li, Liming and Franke, Lude and Burgess, Stephen and Deelen, Patrick and Pers, Tune H and Gr{\o}ndahl, Marie Louise and Andersen, Claus Yding and Pujol, Anna and Lopez-Contreras, Andres J and Daniel, Jeremy A and Stefansson, Kari and Chang-Claude, Jenny and van der Schouw, Yvonne T and Lunetta, Kathryn L and Chasman, Daniel I and Easton, Douglas F and Visser, Jenny A and Ozanne, Susan E and Namekawa, Satoshi H and Solc, Petr and Murabito, Joanne M and Ong, Ken K and Hoffmann, Eva R and Murray, Anna and Roig, Ignasi and Perry, John R B} } @article {9169, title = {Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning.}, journal = {Mol Psychiatry}, year = {2022}, month = {2022 Aug 16}, abstract = {

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

}, issn = {1476-5578}, doi = {10.1038/s41380-022-01710-8}, author = {Lahti, Jari and Tuominen, Samuli and Yang, Qiong and Pergola, Giulio and Ahmad, Shahzad and Amin, Najaf and Armstrong, Nicola J and Beiser, Alexa and Bey, Katharina and Bis, Joshua C and Boerwinkle, Eric and Bressler, Jan and Campbell, Archie and Campbell, Harry and Chen, Qiang and Corley, Janie and Cox, Simon R and Davies, Gail and De Jager, Philip L and Derks, Eske M and Faul, Jessica D and Fitzpatrick, Annette L and Fohner, Alison E and Ford, Ian and Fornage, Myriam and Gerring, Zachary and Grabe, Hans J and Grodstein, Francine and Gudnason, Vilmundur and Simonsick, Eleanor and Holliday, Elizabeth G and Joshi, Peter K and Kajantie, Eero and Kaprio, Jaakko and Karell, Pauliina and Kleineidam, Luca and Knol, Maria J and Kochan, Nicole A and Kwok, John B and Leber, Markus and Lam, Max and Lee, Teresa and Li, Shuo and Loukola, Anu and Luck, Tobias and Marioni, Riccardo E and Mather, Karen A and Medland, Sarah and Mirza, Saira S and Nalls, Mike A and Nho, Kwangsik and O{\textquoteright}Donnell, Adrienne and Oldmeadow, Christopher and Painter, Jodie and Pattie, Alison and Reppermund, Simone and Risacher, Shannon L and Rose, Richard J and Sadashivaiah, Vijay and Scholz, Markus and Satizabal, Claudia L and Schofield, Peter W and Schraut, Katharina E and Scott, Rodney J and Simino, Jeannette and Smith, Albert V and Smith, Jennifer A and Stott, David J and Surakka, Ida and Teumer, Alexander and Thalamuthu, Anbupalam and Trompet, Stella and Turner, Stephen T and van der Lee, Sven J and Villringer, Arno and V{\"o}lker, Uwe and Wilson, Robert S and Wittfeld, Katharina and Vuoksimaa, Eero and Xia, Rui and Yaffe, Kristine and Yu, Lei and Zare, Habil and Zhao, Wei and Ames, David and Attia, John and Bennett, David A and Brodaty, Henry and Chasman, Daniel I and Goldman, Aaron L and Hayward, Caroline and Ikram, M Arfan and Jukema, J Wouter and Kardia, Sharon L R and Lencz, Todd and Loeffler, Markus and Mattay, Venkata S and Palotie, Aarno and Psaty, Bruce M and Ramirez, Alfredo and Ridker, Paul M and Riedel-Heller, Steffi G and Sachdev, Perminder S and Saykin, Andrew J and Scherer, Martin and Schofield, Peter R and Sidney, Stephen and Starr, John M and Trollor, Julian and Ulrich, William and Wagner, Michael and Weir, David R and Wilson, James F and Wright, Margaret J and Weinberger, Daniel R and Debette, Stephanie and Eriksson, Johan G and Mosley, Thomas H and Launer, Lenore J and van Duijn, Cornelia M and Deary, Ian J and Seshadri, Sudha and R{\"a}ikk{\"o}nen, Katri} } @article {9535, title = {Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci.}, journal = {Front Genet}, volume = {14}, year = {2023}, month = {2023}, pages = {1235337}, abstract = {

Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( < 5 {\texttimes} 10) and suggestive ( < 1 {\texttimes} 10) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (), brain (), and liver () biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

}, issn = {1664-8021}, doi = {10.3389/fgene.2023.1235337}, author = {de Las Fuentes, Lisa and Schwander, Karen L and Brown, Michael R and Bentley, Amy R and Winkler, Thomas W and Sung, Yun Ju and Munroe, Patricia B and Miller, Clint L and Aschard, Hugo and Aslibekyan, Stella and Bartz, Traci M and Bielak, Lawrence F and Chai, Jin Fang and Cheng, Ching-Yu and Dorajoo, Rajkumar and Feitosa, Mary F and Guo, Xiuqing and Hartwig, Fernando P and Horimoto, Andrea and Kolcic, Ivana and Lim, Elise and Liu, Yongmei and Manning, Alisa K and Marten, Jonathan and Musani, Solomon K and Noordam, Raymond and Padmanabhan, Sandosh and Rankinen, Tuomo and Richard, Melissa A and Ridker, Paul M and Smith, Albert V and Vojinovic, Dina and Zonderman, Alan B and Alver, Maris and Boissel, Mathilde and Christensen, Kaare and Freedman, Barry I and Gao, Chuan and Giulianini, Franco and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Kuhnel, Brigitte and Laguzzi, Federica and Li, Xiaoyin and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Poveda, Alaitz and Rauramaa, Rainer and Riaz, Muhammad and Robino, Antonietta and Sofer, Tamar and Takeuchi, Fumihiko and Tayo, Bamidele O and van der Most, Peter J and Verweij, Niek and Ware, Erin B and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Zhan, Yiqiang and Amin, Najaf and Arking, Dan E and Ballantyne, Christie and Boerwinkle, Eric and Brody, Jennifer A and Broeckel, Ulrich and Campbell, Archie and Canouil, Micka{\"e}l and Chai, Xiaoran and Chen, Yii-Der Ida and Chen, Xu and Chitrala, Kumaraswamy Naidu and Concas, Maria Pina and de Faire, Ulf and de Mutsert, Ren{\'e}e and de Silva, H Janaka and de Vries, Paul S and Do, Ahn and Faul, Jessica D and Fisher, Virginia and Floyd, James S and Forrester, Terrence and Friedlander, Yechiel and Girotto, Giorgia and Gu, C Charles and Hallmans, G{\"o}ran and Heikkinen, Sami and Heng, Chew-Kiat and Homuth, Georg and Hunt, Steven and Ikram, M Arfan and Jacobs, David R and Kavousi, Maryam and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Komulainen, Pirjo and Langefeld, Carl D and Liang, Jingjing and Liu, Kiang and Liu, Jianjun and Lohman, Kurt and M{\"a}gi, Reedik and Manichaikul, Ani W and McKenzie, Colin A and Meitinger, Thomas and Milaneschi, Yuri and Nauck, Matthias and Nelson, Christopher P and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Pereira, Alexandre C and Perls, Thomas and Peters, Annette and Polasek, Ozren and Raitakari, Olli T and Rice, Kenneth and Rice, Treva K and Rich, Stephen S and Sabanayagam, Charumathi and Schreiner, Pamela J and Shu, Xiao-Ou and Sidney, Stephen and Sims, Mario and Smith, Jennifer A and Starr, John M and Strauch, Konstantin and Tai, E Shyong and Taylor, Kent D and Tsai, Michael Y and Uitterlinden, Andr{\'e} G and van Heemst, Diana and Waldenberger, Melanie and Wang, Ya-Xing and Wei, Wen-Bin and Wilson, Gregory and Xuan, Deng and Yao, Jie and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Becker, Diane M and Bonnefond, Am{\'e}lie and Bowden, Donald W and Cooper, Richard S and Deary, Ian J and Divers, Jasmin and Esko, T{\~o}nu and Franks, Paul W and Froguel, Philippe and Gieger, Christian and Jonas, Jost B and Kato, Norihiro and Lakka, Timo A and Leander, Karin and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and North, Kari E and Ntalla, Ioanna and Penninx, Brenda and Samani, Nilesh J and Snieder, Harold and Spedicati, Beatrice and van der Harst, Pim and V{\"o}lzke, Henry and Wagenknecht, Lynne E and Weir, David R and Wojczynski, Mary K and Wu, Tangchun and Zheng, Wei and Zhu, Xiaofeng and Bouchard, Claude and Chasman, Daniel I and Evans, Michele K and Fox, Ervin R and Gudnason, Vilmundur and Hayward, Caroline and Horta, Bernardo L and Kardia, Sharon L R and Krieger, Jose Eduardo and Mook-Kanamori, Dennis O and Peyser, Patricia A and Province, Michael M and Psaty, Bruce M and Rudan, Igor and Sim, Xueling and Smith, Blair H and van Dam, Rob M and van Duijn, Cornelia M and Wong, Tien Yin and Arnett, Donna K and Rao, Dabeeru C and Gauderman, James and Liu, Ching-Ti and Morrison, Alanna C and Rotter, Jerome I and Fornage, Myriam} } @article {9419, title = {The genetic determinants of recurrent somatic mutations in 43,693 blood genomes.}, journal = {Sci Adv}, volume = {9}, year = {2023}, month = {2023 Apr 28}, pages = {eabm4945}, abstract = {

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

}, keywords = {Germ-Line Mutation, Hematopoiesis, Humans, Middle Aged, Mutation, Mutation, Missense, Phenotype}, issn = {2375-2548}, doi = {10.1126/sciadv.abm4945}, author = {Weinstock, Joshua S and Laurie, Cecelia A and Broome, Jai G and Taylor, Kent D and Guo, Xiuqing and Shuldiner, Alan R and O{\textquoteright}Connell, Jeffrey R and Lewis, Joshua P and Boerwinkle, Eric and Barnes, Kathleen C and Chami, Nathalie and Kenny, Eimear E and Loos, Ruth J F and Fornage, Myriam and Redline, Susan and Cade, Brian E and Gilliland, Frank D and Chen, Zhanghua and Gauderman, W James and Kumar, Rajesh and Grammer, Leslie and Schleimer, Robert P and Psaty, Bruce M and Bis, Joshua C and Brody, Jennifer A and Silverman, Edwin K and Yun, Jeong H and Qiao, Dandi and Weiss, Scott T and Lasky-Su, Jessica and DeMeo, Dawn L and Palmer, Nicholette D and Freedman, Barry I and Bowden, Donald W and Cho, Michael H and Vasan, Ramachandran S and Johnson, Andrew D and Yanek, Lisa R and Becker, Lewis C and Kardia, Sharon and He, Jiang and Kaplan, Robert and Heckbert, Susan R and Smith, Nicholas L and Wiggins, Kerri L and Arnett, Donna K and Irvin, Marguerite R and Tiwari, Hemant and Correa, Adolfo and Raffield, Laura M and Gao, Yan and de Andrade, Mariza and Rotter, Jerome I and Rich, Stephen S and Manichaikul, Ani W and Konkle, Barbara A and Johnsen, Jill M and Wheeler, Marsha M and Custer, Brian S and Duggirala, Ravindranath and Curran, Joanne E and Blangero, John and Gui, Hongsheng and Xiao, Shujie and Williams, L Keoki and Meyers, Deborah A and Li, Xingnan and Ortega, Victor and McGarvey, Stephen and Gu, C Charles and Chen, Yii-Der Ida and Lee, Wen-Jane and Shoemaker, M Benjamin and Darbar, Dawood and Roden, Dan and Albert, Christine and Kooperberg, Charles and Desai, Pinkal and Blackwell, Thomas W and Abecasis, Goncalo R and Smith, Albert V and Kang, Hyun M and Mathias, Rasika and Natarajan, Pradeep and Jaiswal, Siddhartha and Reiner, Alexander P and Bick, Alexander G} }