@article {6548, title = {Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e99798}, abstract = {

BACKGROUND: Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk.

METHODS AND RESULTS: We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] >= 1\%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF<= 1\% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026).

CONCLUSION: Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.

}, keywords = {Cell Adhesion Molecules, Neuronal, European Continental Ancestry Group, Female, Genetic Association Studies, Genetic Heterogeneity, Humans, Introns, Ischemia, Male, Myocardial Infarction, Polymorphism, Single Nucleotide, Prospective Studies, Sequence Analysis, DNA}, issn = {1932-6203}, doi = {10.1371/journal.pone.0099798}, author = {Bis, Joshua C and DeStefano, Anita and Liu, Xiaoming and Brody, Jennifer A and Choi, Seung Hoan and Verhaaren, Benjamin F J and Debette, Stephanie and Ikram, M Arfan and Shahar, Eyal and Butler, Kenneth R and Gottesman, Rebecca F and Muzny, Donna and Kovar, Christie L and Psaty, Bruce M and Hofman, Albert and Lumley, Thomas and Gupta, Mayetri and Wolf, Philip A and van Duijn, Cornelia and Gibbs, Richard A and Mosley, Thomas H and Longstreth, W T and Boerwinkle, Eric and Seshadri, Sudha and Fornage, Myriam} } @article {6220, title = {Predicting stroke through genetic risk functions: the CHARGE Risk Score Project.}, journal = {Stroke}, volume = {45}, year = {2014}, month = {2014 Feb}, pages = {403-12}, abstract = {

BACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.

METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged >=55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke.

RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3{\texttimes}10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7{\texttimes}10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)).

CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Area Under Curve, Case-Control Studies, Cohort Studies, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Regression Analysis, Risk Factors, ROC Curve, Sex Factors, Stroke}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.113.003044}, author = {Ibrahim-Verbaas, Carla A and Fornage, Myriam and Bis, Joshua C and Choi, Seung Hoan and Psaty, Bruce M and Meigs, James B and Rao, Madhu and Nalls, Mike and Fontes, Jo{\~a}o D and O{\textquoteright}Donnell, Christopher J and Kathiresan, Sekar and Ehret, Georg B and Fox, Caroline S and Malik, Rainer and Dichgans, Martin and Schmidt, Helena and Lahti, Jari and Heckbert, Susan R and Lumley, Thomas and Rice, Kenneth and Rotter, Jerome I and Taylor, Kent D and Folsom, Aaron R and Boerwinkle, Eric and Rosamond, Wayne D and Shahar, Eyal and Gottesman, Rebecca F and Koudstaal, Peter J and Amin, Najaf and Wieberdink, Renske G and Dehghan, Abbas and Hofman, Albert and Uitterlinden, Andr{\'e} G and DeStefano, Anita L and Debette, Stephanie and Xue, Luting and Beiser, Alexa and Wolf, Philip A and DeCarli, Charles and Ikram, M Arfan and Seshadri, Sudha and Mosley, Thomas H and Longstreth, W T and van Duijn, Cornelia M and Launer, Lenore J} } @article {6684, title = {Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.}, journal = {Biol Psychiatry}, volume = {77}, year = {2015}, month = {2015 Apr 15}, pages = {749-63}, abstract = {

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.

METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged >=45 years. Replication of suggestive associations (p < 5 {\texttimes} 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.

RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 {\texttimes} 10(-10)) and replication cohorts (p = 5.65 {\texttimes} 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 {\texttimes} 10(-8), and rs6813517 [SPOCK3], p = 2.58 {\texttimes} 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.

CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

}, keywords = {Aged, Aged, 80 and over, Aging, Apolipoproteins E, Claudin-5, Cohort Studies, Female, Genome-Wide Association Study, Genotype, Humans, Male, Memory Disorders, Middle Aged, Polymorphism, Single Nucleotide, Proteins, Proteoglycans, Regression Analysis, Sulfotransferases, Verbal Learning}, issn = {1873-2402}, doi = {10.1016/j.biopsych.2014.08.027}, author = {Debette, Stephanie and Ibrahim Verbaas, Carla A and Bressler, Jan and Schuur, Maaike and Smith, Albert and Bis, Joshua C and Davies, Gail and Wolf, Christiane and Gudnason, Vilmundur and Chibnik, Lori B and Yang, Qiong and DeStefano, Anita L and de Quervain, Dominique J F and Srikanth, Velandai and Lahti, Jari and Grabe, Hans J and Smith, Jennifer A and Priebe, Lutz and Yu, Lei and Karbalai, Nazanin and Hayward, Caroline and Wilson, James F and Campbell, Harry and Petrovic, Katja and Fornage, Myriam and Chauhan, Ganesh and Yeo, Robin and Boxall, Ruth and Becker, James and Stegle, Oliver and Mather, Karen A and Chouraki, Vincent and Sun, Qi and Rose, Lynda M and Resnick, Susan and Oldmeadow, Christopher and Kirin, Mirna and Wright, Alan F and Jonsdottir, Maria K and Au, Rhoda and Becker, Albert and Amin, Najaf and Nalls, Mike A and Turner, Stephen T and Kardia, Sharon L R and Oostra, Ben and Windham, Gwen and Coker, Laura H and Zhao, Wei and Knopman, David S and Heiss, Gerardo and Griswold, Michael E and Gottesman, Rebecca F and Vitart, Veronique and Hastie, Nicholas D and Zgaga, Lina and Rudan, Igor and Polasek, Ozren and Holliday, Elizabeth G and Schofield, Peter and Choi, Seung Hoan and Tanaka, Toshiko and An, Yang and Perry, Rodney T and Kennedy, Richard E and Sale, Mich{\`e}le M and Wang, Jing and Wadley, Virginia G and Liewald, David C and Ridker, Paul M and Gow, Alan J and Pattie, Alison and Starr, John M and Porteous, David and Liu, Xuan and Thomson, Russell and Armstrong, Nicola J and Eiriksdottir, Gudny and Assareh, Arezoo A and Kochan, Nicole A and Widen, Elisabeth and Palotie, Aarno and Hsieh, Yi-Chen and Eriksson, Johan G and Vogler, Christian and van Swieten, John C and Shulman, Joshua M and Beiser, Alexa and Rotter, Jerome and Schmidt, Carsten O and Hoffmann, Wolfgang and N{\"o}then, Markus M and Ferrucci, Luigi and Attia, John and Uitterlinden, Andr{\'e} G and Amouyel, Philippe and Dartigues, Jean-Fran{\c c}ois and Amieva, H{\'e}l{\`e}ne and R{\"a}ikk{\"o}nen, Katri and Garcia, Melissa and Wolf, Philip A and Hofman, Albert and Longstreth, W T and Psaty, Bruce M and Boerwinkle, Eric and DeJager, Philip L and Sachdev, Perminder S and Schmidt, Reinhold and Breteler, Monique M B and Teumer, Alexander and Lopez, Oscar L and Cichon, Sven and Chasman, Daniel I and Grodstein, Francine and M{\"u}ller-Myhsok, Bertram and Tzourio, Christophe and Papassotiropoulos, Andreas and Bennett, David A and Ikram, M Arfan and Deary, Ian J and van Duijn, Cornelia M and Launer, Lenore and Fitzpatrick, Annette L and Seshadri, Sudha and Mosley, Thomas H} } @article {7185, title = {Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer{\textquoteright}s Disease.}, journal = {J Alzheimers Dis}, volume = {53}, year = {2016}, month = {2016 Jun 18}, pages = {921-32}, abstract = {

Effective prevention of Alzheimer{\textquoteright}s disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOEɛ4. In eight prospective cohorts included in the International Genomics of Alzheimer{\textquoteright}s Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17\% increase in AD risk (pooled HR = 1.17; 95\% CI =   [1.13-1.21] per standard deviation increase in GRS; p-value =  2.86{\texttimes}10-16). This association was stronger among persons with at least one APOEɛ4 allele (HRGRS = 1.24; 95\% CI =   [1.15-1.34]) than in others (HRGRS = 1.13; 95\% CI =   [1.08-1.18]; pinteraction = 3.45{\texttimes}10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOEɛ4, and education (Δ-Cindex =  0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOEɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

}, issn = {1875-8908}, doi = {10.3233/JAD-150749}, author = {Chouraki, Vincent and Reitz, Christiane and Maury, Fleur and Bis, Joshua C and Bellenguez, C{\'e}line and Yu, Lei and Jakobsdottir, Johanna and Mukherjee, Shubhabrata and Adams, Hieab H and Choi, Seung Hoan and Larson, Eric B and Fitzpatrick, Annette and Uitterlinden, Andr{\'e} G and De Jager, Philip L and Hofman, Albert and Gudnason, Vilmundur and Vardarajan, Badri and Ibrahim-Verbaas, Carla and van der Lee, Sven J and Lopez, Oscar and Dartigues, Jean-Fran{\c c}ois and Berr, Claudine and Amouyel, Philippe and Bennett, David A and van Duijn, Cornelia and DeStefano, Anita L and Launer, Lenore J and Ikram, M Arfan and Crane, Paul K and Lambert, Jean-Charles and Mayeux, Richard and Seshadri, Sudha} } @article {7396, title = {Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Jun}, pages = {946-952}, abstract = {

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

}, issn = {1546-1718}, doi = {10.1038/ng.3843}, author = {Christophersen, Ingrid E and Rienstra, Michiel and Roselli, Carolina and Yin, Xiaoyan and Geelhoed, Bastiaan and Barnard, John and Lin, Honghuang and Arking, Dan E and Smith, Albert V and Albert, Christine M and Chaffin, Mark and Tucker, Nathan R and Li, Molong and Klarin, Derek and Bihlmeyer, Nathan A and Low, Siew-Kee and Weeke, Peter E and M{\"u}ller-Nurasyid, Martina and Smith, J Gustav and Brody, Jennifer A and Niemeijer, Maartje N and D{\"o}rr, Marcus and Trompet, Stella and Huffman, Jennifer and Gustafsson, Stefan and Schurmann, Claudia and Kleber, Marcus E and Lyytik{\"a}inen, Leo-Pekka and Sepp{\"a}l{\"a}, Ilkka and Malik, Rainer and Horimoto, Andrea R V R and Perez, Marco and Sinisalo, Juha and Aeschbacher, Stefanie and Th{\'e}riault, S{\'e}bastien and Yao, Jie and Radmanesh, Farid and Weiss, Stefan and Teumer, Alexander and Choi, Seung Hoan and Weng, Lu-Chen and Clauss, Sebastian and Deo, Rajat and Rader, Daniel J and Shah, Svati H and Sun, Albert and Hopewell, Jemma C and Debette, Stephanie and Chauhan, Ganesh and Yang, Qiong and Worrall, Bradford B and Par{\'e}, Guillaume and Kamatani, Yoichiro and Hagemeijer, Yanick P and Verweij, Niek and Siland, Joylene E and Kubo, Michiaki and Smith, Jonathan D and Van Wagoner, David R and Bis, Joshua C and Perz, Siegfried and Psaty, Bruce M and Ridker, Paul M and Magnani, Jared W and Harris, Tamara B and Launer, Lenore J and Shoemaker, M Benjamin and Padmanabhan, Sandosh and Haessler, Jeffrey and Bartz, Traci M and Waldenberger, Melanie and Lichtner, Peter and Arendt, Marina and Krieger, Jose E and K{\"a}h{\"o}nen, Mika and Risch, Lorenz and Mansur, Alfredo J and Peters, Annette and Smith, Blair H and Lind, Lars and Scott, Stuart A and Lu, Yingchang and Bottinger, Erwin B and Hernesniemi, Jussi and Lindgren, Cecilia M and Wong, Jorge A and Huang, Jie and Eskola, Markku and Morris, Andrew P and Ford, Ian and Reiner, Alex P and Delgado, Graciela and Chen, Lin Y and Chen, Yii-Der Ida and Sandhu, Roopinder K and Li, Man and Boerwinkle, Eric and Eisele, Lewin and Lannfelt, Lars and Rost, Natalia and Anderson, Christopher D and Taylor, Kent D and Campbell, Archie and Magnusson, Patrik K and Porteous, David and Hocking, Lynne J and Vlachopoulou, Efthymia and Pedersen, Nancy L and Nikus, Kjell and Orho-Melander, Marju and Hamsten, Anders and Heeringa, Jan and Denny, Joshua C and Kriebel, Jennifer and Darbar, Dawood and Newton-Cheh, Christopher and Shaffer, Christian and Macfarlane, Peter W and Heilmann-Heimbach, Stefanie and Almgren, Peter and Huang, Paul L and Sotoodehnia, Nona and Soliman, Elsayed Z and Uitterlinden, Andr{\'e} G and Hofman, Albert and Franco, Oscar H and V{\"o}lker, Uwe and J{\"o}ckel, Karl-Heinz and Sinner, Moritz F and Lin, Henry J and Guo, Xiuqing and Dichgans, Martin and Ingelsson, Erik and Kooperberg, Charles and Melander, Olle and Loos, Ruth J F and Laurikka, Jari and Conen, David and Rosand, Jonathan and van der Harst, Pim and Lokki, Marja-Liisa and Kathiresan, Sekar and Pereira, Alexandre and Jukema, J Wouter and Hayward, Caroline and Rotter, Jerome I and M{\"a}rz, Winfried and Lehtim{\"a}ki, Terho and Stricker, Bruno H and Chung, Mina K and Felix, Stephan B and Gudnason, Vilmundur and Alonso, Alvaro and Roden, Dan M and K{\"a}{\"a}b, Stefan and Chasman, Daniel I and Heckbert, Susan R and Benjamin, Emelia J and Tanaka, Toshihiro and Lunetta, Kathryn L and Lubitz, Steven A and Ellinor, Patrick T} } @article {7683, title = {Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Apr}, pages = {524-537}, abstract = {

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and~using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0058-3}, author = {Malik, Rainer and Chauhan, Ganesh and Traylor, Matthew and Sargurupremraj, Muralidharan and Okada, Yukinori and Mishra, Aniket and Rutten-Jacobs, Loes and Giese, Anne-Katrin and van der Laan, Sander W and Gretarsdottir, Solveig and Anderson, Christopher D and Chong, Michael and Adams, Hieab H H and Ago, Tetsuro and Almgren, Peter and Amouyel, Philippe and Ay, Hakan and Bartz, Traci M and Benavente, Oscar R and Bevan, Steve and Boncoraglio, Giorgio B and Brown, Robert D and Butterworth, Adam S and Carrera, Caty and Carty, Cara L and Chasman, Daniel I and Chen, Wei-Min and Cole, John W and Correa, Adolfo and Cotlarciuc, Ioana and Cruchaga, Carlos and Danesh, John and de Bakker, Paul I W and DeStefano, Anita L and den Hoed, Marcel and Duan, Qing and Engelter, Stefan T and Falcone, Guido J and Gottesman, Rebecca F and Grewal, Raji P and Gudnason, Vilmundur and Gustafsson, Stefan and Haessler, Jeffrey and Harris, Tamara B and Hassan, Ahamad and Havulinna, Aki S and Heckbert, Susan R and Holliday, Elizabeth G and Howard, George and Hsu, Fang-Chi and Hyacinth, Hyacinth I and Ikram, M Arfan and Ingelsson, Erik and Irvin, Marguerite R and Jian, Xueqiu and Jimenez-Conde, Jordi and Johnson, Julie A and Jukema, J Wouter and Kanai, Masahiro and Keene, Keith L and Kissela, Brett M and Kleindorfer, Dawn O and Kooperberg, Charles and Kubo, Michiaki and Lange, Leslie A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lee, Jin-Moo and Lemmens, Robin and Leys, Didier and Lewis, Cathryn M and Lin, Wei-Yu and Lindgren, Arne G and Lorentzen, Erik and Magnusson, Patrik K and Maguire, Jane and Manichaikul, Ani and McArdle, Patrick F and Meschia, James F and Mitchell, Braxton D and Mosley, Thomas H and Nalls, Michael A and Ninomiya, Toshiharu and O{\textquoteright}Donnell, Martin J and Psaty, Bruce M and Pulit, Sara L and Rannikmae, Kristiina and Reiner, Alexander P and Rexrode, Kathryn M and Rice, Kenneth and Rich, Stephen S and Ridker, Paul M and Rost, Natalia S and Rothwell, Peter M and Rotter, Jerome I and Rundek, Tatjana and Sacco, Ralph L and Sakaue, Saori and Sale, Mich{\`e}le M and Salomaa, Veikko and Sapkota, Bishwa R and Schmidt, Reinhold and Schmidt, Carsten O and Schminke, Ulf and Sharma, Pankaj and Slowik, Agnieszka and Sudlow, Cathie L M and Tanislav, Christian and Tatlisumak, Turgut and Taylor, Kent D and Thijs, Vincent N S and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tiedt, Steffen and Trompet, Stella and Tzourio, Christophe and van Duijn, Cornelia M and Walters, Matthew and Wareham, Nicholas J and Wassertheil-Smoller, Sylvia and Wilson, James G and Wiggins, Kerri L and Yang, Qiong and Yusuf, Salim and Bis, Joshua C and Pastinen, Tomi and Ruusalepp, Arno and Schadt, Eric E and Koplev, Simon and Bj{\"o}rkegren, Johan L M and Codoni, Veronica and Civelek, Mete and Smith, Nicholas L and Tr{\'e}gou{\"e}t, David A and Christophersen, Ingrid E and Roselli, Carolina and Lubitz, Steven A and Ellinor, Patrick T and Tai, E Shyong and Kooner, Jaspal S and Kato, Norihiro and He, Jiang and van der Harst, Pim and Elliott, Paul and Chambers, John C and Takeuchi, Fumihiko and Johnson, Andrew D and Sanghera, Dharambir K and Melander, Olle and Jern, Christina and Strbian, Daniel and Fernandez-Cadenas, Israel and Longstreth, W T and Rolfs, Arndt and Hata, Jun and Woo, Daniel and Rosand, Jonathan and Par{\'e}, Guillaume and Hopewell, Jemma C and Saleheen, Danish and Stefansson, Kari and Worrall, Bradford B and Kittner, Steven J and Seshadri, Sudha and Fornage, Myriam and Markus, Hugh S and Howson, Joanna M M and Kamatani, Yoichiro and Debette, Stephanie and Dichgans, Martin and Malik, Rainer and Chauhan, Ganesh and Traylor, Matthew and Sargurupremraj, Muralidharan and Okada, Yukinori and Mishra, Aniket and Rutten-Jacobs, Loes and Giese, Anne-Katrin and van der Laan, Sander W and Gretarsdottir, Solveig and Anderson, Christopher D and Chong, Michael and Adams, Hieab H H and Ago, Tetsuro and Almgren, Peter and Amouyel, Philippe and Ay, Hakan and Bartz, Traci M and Benavente, Oscar R and Bevan, Steve and Boncoraglio, Giorgio B and Brown, Robert D and Butterworth, Adam S and Carrera, Caty and Carty, Cara L and Chasman, Daniel I and Chen, Wei-Min and Cole, John W and Correa, Adolfo and Cotlarciuc, Ioana and Cruchaga, Carlos and Danesh, John and de Bakker, Paul I W and DeStefano, Anita L and Hoed, Marcel den and Duan, Qing and Engelter, Stefan T and Falcone, Guido J and Gottesman, Rebecca F and Grewal, Raji P and Gudnason, Vilmundur and Gustafsson, Stefan and Haessler, Jeffrey and Harris, Tamara B and Hassan, Ahamad and Havulinna, Aki S and Heckbert, Susan R and Holliday, Elizabeth G and Howard, George and Hsu, Fang-Chi and Hyacinth, Hyacinth I and Ikram, M Arfan and Ingelsson, Erik and Irvin, Marguerite R and Jian, Xueqiu and Jimenez-Conde, Jordi and Johnson, Julie A and Jukema, J Wouter and Kanai, Masahiro and Keene, Keith L and Kissela, Brett M and Kleindorfer, Dawn O and Kooperberg, Charles and Kubo, Michiaki and Lange, Leslie A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lee, Jin-Moo and Lemmens, Robin and Leys, Didier and Lewis, Cathryn M and Lin, Wei-Yu and Lindgren, Arne G and Lorentzen, Erik and Magnusson, Patrik K and Maguire, Jane and Manichaikul, Ani and McArdle, Patrick F and Meschia, James F and Mitchell, Braxton D and Mosley, Thomas H and Nalls, Michael A and Ninomiya, Toshiharu and O{\textquoteright}Donnell, Martin J and Psaty, Bruce M and Pulit, Sara L and Rannikmae, Kristiina and Reiner, Alexander P and Rexrode, Kathryn M and Rice, Kenneth and Rich, Stephen S and Ridker, Paul M and Rost, Natalia S and Rothwell, Peter M and Rotter, Jerome I and Rundek, Tatjana and Sacco, Ralph L and Sakaue, Saori and Sale, Mich{\`e}le M and Salomaa, Veikko and Sapkota, Bishwa R and Schmidt, Reinhold and Schmidt, Carsten O and Schminke, Ulf and Sharma, Pankaj and Slowik, Agnieszka and Sudlow, Cathie L M and Tanislav, Christian and Tatlisumak, Turgut and Taylor, Kent D and Thijs, Vincent N S and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tiedt, Steffen and Trompet, Stella and Tzourio, Christophe and van Duijn, Cornelia M and Walters, Matthew and Wareham, Nicholas J and Wassertheil-Smoller, Sylvia and Wilson, James G and Wiggins, Kerri L and Yang, Qiong and Yusuf, Salim and Amin, Najaf and Aparicio, Hugo S and Arnett, Donna K and Attia, John and Beiser, Alexa S and Berr, Claudine and Buring, Julie E and Bustamante, Mariana and Caso, Valeria and Cheng, Yu-Ching and Choi, Seung Hoan and Chowhan, Ayesha and Cullell, Natalia and Dartigues, Jean-Fran{\c c}ois and Delavaran, Hossein and Delgado, Pilar and D{\"o}rr, Marcus and Engstr{\"o}m, Gunnar and Ford, Ian and Gurpreet, Wander S and Hamsten, Anders and Heitsch, Laura and Hozawa, Atsushi and Ibanez, Laura and Ilinca, Andreea and Ingelsson, Martin and Iwasaki, Motoki and Jackson, Rebecca D and Jood, Katarina and Jousilahti, Pekka and Kaffashian, Sara and Kalra, Lalit and Kamouchi, Masahiro and Kitazono, Takanari and Kjartansson, Olafur and Kloss, Manja and Koudstaal, Peter J and Krupinski, Jerzy and Labovitz, Daniel L and Laurie, Cathy C and Levi, Christopher R and Li, Linxin and Lind, Lars and Lindgren, Cecilia M and Lioutas, Vasileios and Liu, Yong Mei and Lopez, Oscar L and Makoto, Hirata and Martinez-Majander, Nicolas and Matsuda, Koichi and Minegishi, Naoko and Montaner, Joan and Morris, Andrew P and Mui{\~n}o, Elena and M{\"u}ller-Nurasyid, Martina and Norrving, Bo and Ogishima, Soichi and Parati, Eugenio A and Peddareddygari, Leema Reddy and Pedersen, Nancy L and Pera, Joanna and Perola, Markus and Pezzini, Alessandro and Pileggi, Silvana and Rabionet, Raquel and Riba-Llena, Iolanda and Ribas{\'e}s, Marta and Romero, Jose R and Roquer, Jaume and Rudd, Anthony G and Sarin, Antti-Pekka and Sarju, Ralhan and Sarnowski, Chloe and Sasaki, Makoto and Satizabal, Claudia L and Satoh, Mamoru and Sattar, Naveed and Sawada, Norie and Sibolt, Gerli and Sigurdsson, {\'A}sgeir and Smith, Albert and Sobue, Kenji and Soriano-T{\'a}rraga, Carolina and Stanne, Tara and Stine, O Colin and Stott, David J and Strauch, Konstantin and Takai, Takako and Tanaka, Hideo and Tanno, Kozo and Teumer, Alexander and Tomppo, Liisa and Torres-Aguila, Nuria P and Touze, Emmanuel and Tsugane, Shoichiro and Uitterlinden, Andr{\'e} G and Valdimarsson, Einar M and van der Lee, Sven J and V{\"o}lzke, Henry and Wakai, Kenji and Weir, David and Williams, Stephen R and Wolfe, Charles D A and Wong, Quenna and Xu, Huichun and Yamaji, Taiki and Sanghera, Dharambir K and Melander, Olle and Jern, Christina and Strbian, Daniel and Fernandez-Cadenas, Israel and Longstreth, W T and Rolfs, Arndt and Hata, Jun and Woo, Daniel and Rosand, Jonathan and Par{\'e}, Guillaume and Hopewell, Jemma C and Saleheen, Danish and Stefansson, Kari and Worrall, Bradford B and Kittner, Steven J and Seshadri, Sudha and Fornage, Myriam and Markus, Hugh S and Howson, Joanna M M and Kamatani, Yoichiro and Debette, Stephanie and Dichgans, Martin} } @article {7811, title = {Multi-ethnic genome-wide association study for atrial fibrillation.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Sep}, pages = {1225-1233}, abstract = {

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0133-9}, author = {Roselli, Carolina and Chaffin, Mark D and Weng, Lu-Chen and Aeschbacher, Stefanie and Ahlberg, Gustav and Albert, Christine M and Almgren, Peter and Alonso, Alvaro and Anderson, Christopher D and Aragam, Krishna G and Arking, Dan E and Barnard, John and Bartz, Traci M and Benjamin, Emelia J and Bihlmeyer, Nathan A and Bis, Joshua C and Bloom, Heather L and Boerwinkle, Eric and Bottinger, Erwin B and Brody, Jennifer A and Calkins, Hugh and Campbell, Archie and Cappola, Thomas P and Carlquist, John and Chasman, Daniel I and Chen, Lin Y and Chen, Yii-Der Ida and Choi, Eue-Keun and Choi, Seung Hoan and Christophersen, Ingrid E and Chung, Mina K and Cole, John W and Conen, David and Cook, James and Crijns, Harry J and Cutler, Michael J and Damrauer, Scott M and Daniels, Brian R and Darbar, Dawood and Delgado, Graciela and Denny, Joshua C and Dichgans, Martin and D{\"o}rr, Marcus and Dudink, Elton A and Dudley, Samuel C and Esa, Nada and Esko, T{\~o}nu and Eskola, Markku and Fatkin, Diane and Felix, Stephan B and Ford, Ian and Franco, Oscar H and Geelhoed, Bastiaan and Grewal, Raji P and Gudnason, Vilmundur and Guo, Xiuqing and Gupta, Namrata and Gustafsson, Stefan and Gutmann, Rebecca and Hamsten, Anders and Harris, Tamara B and Hayward, Caroline and Heckbert, Susan R and Hernesniemi, Jussi and Hocking, Lynne J and Hofman, Albert and Horimoto, Andrea R V R and Huang, Jie and Huang, Paul L and Huffman, Jennifer and Ingelsson, Erik and Ipek, Esra Gucuk and Ito, Kaoru and Jimenez-Conde, Jordi and Johnson, Renee and Jukema, J Wouter and K{\"a}{\"a}b, Stefan and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kane, John P and Kastrati, Adnan and Kathiresan, Sekar and Katschnig-Winter, Petra and Kavousi, Maryam and Kessler, Thorsten and Kietselaer, Bas L and Kirchhof, Paulus and Kleber, Marcus E and Knight, Stacey and Krieger, Jose E and Kubo, Michiaki and Launer, Lenore J and Laurikka, Jari and Lehtim{\"a}ki, Terho and Leineweber, Kirsten and Lemaitre, Rozenn N and Li, Man and Lim, Hong Euy and Lin, Henry J and Lin, Honghuang and Lind, Lars and Lindgren, Cecilia M and Lokki, Marja-Liisa and London, Barry and Loos, Ruth J F and Low, Siew-Kee and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and Macfarlane, Peter W and Magnusson, Patrik K and Mahajan, Anubha and Malik, Rainer and Mansur, Alfredo J and Marcus, Gregory M and Margolin, Lauren and Margulies, Kenneth B and M{\"a}rz, Winfried and McManus, David D and Melander, Olle and Mohanty, Sanghamitra and Montgomery, Jay A and Morley, Michael P and Morris, Andrew P and M{\"u}ller-Nurasyid, Martina and Natale, Andrea and Nazarian, Saman and Neumann, Benjamin and Newton-Cheh, Christopher and Niemeijer, Maartje N and Nikus, Kjell and Nilsson, Peter and Noordam, Raymond and Oellers, Heidi and Olesen, Morten S and Orho-Melander, Marju and Padmanabhan, Sandosh and Pak, Hui-Nam and Par{\'e}, Guillaume and Pedersen, Nancy L and Pera, Joanna and Pereira, Alexandre and Porteous, David and Psaty, Bruce M and Pulit, Sara L and Pullinger, Clive R and Rader, Daniel J and Refsgaard, Lena and Ribas{\'e}s, Marta and Ridker, Paul M and Rienstra, Michiel and Risch, Lorenz and Roden, Dan M and Rosand, Jonathan and Rosenberg, Michael A and Rost, Natalia and Rotter, Jerome I and Saba, Samir and Sandhu, Roopinder K and Schnabel, Renate B and Schramm, Katharina and Schunkert, Heribert and Schurman, Claudia and Scott, Stuart A and Sepp{\"a}l{\"a}, Ilkka and Shaffer, Christian and Shah, Svati and Shalaby, Alaa A and Shim, Jaemin and Shoemaker, M Benjamin and Siland, Joylene E and Sinisalo, Juha and Sinner, Moritz F and Slowik, Agnieszka and Smith, Albert V and Smith, Blair H and Smith, J Gustav and Smith, Jonathan D and Smith, Nicholas L and Soliman, Elsayed Z and Sotoodehnia, Nona and Stricker, Bruno H and Sun, Albert and Sun, Han and Svendsen, Jesper H and Tanaka, Toshihiro and Tanriverdi, Kahraman and Taylor, Kent D and Teder-Laving, Maris and Teumer, Alexander and Th{\'e}riault, S{\'e}bastien and Trompet, Stella and Tucker, Nathan R and Tveit, Arnljot and Uitterlinden, Andr{\'e} G and van der Harst, Pim and Van Gelder, Isabelle C and Van Wagoner, David R and Verweij, Niek and Vlachopoulou, Efthymia and V{\"o}lker, Uwe and Wang, Biqi and Weeke, Peter E and Weijs, Bob and Weiss, Raul and Weiss, Stefan and Wells, Quinn S and Wiggins, Kerri L and Wong, Jorge A and Woo, Daniel and Worrall, Bradford B and Yang, Pil-Sung and Yao, Jie and Yoneda, Zachary T and Zeller, Tanja and Zeng, Lingyao and Lubitz, Steven A and Lunetta, Kathryn L and Ellinor, Patrick T} } @article {8368, title = {Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 May 21}, pages = {2542}, abstract = {

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5\% to 62.6\%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

}, issn = {2041-1723}, doi = {10.1038/s41467-020-15706-x}, author = {Ntalla, Ioanna and Weng, Lu-Chen and Cartwright, James H and Hall, Amelia Weber and Sveinbjornsson, Gardar and Tucker, Nathan R and Choi, Seung Hoan and Chaffin, Mark D and Roselli, Carolina and Barnes, Michael R and Mifsud, Borbala and Warren, Helen R and Hayward, Caroline and Marten, Jonathan and Cranley, James J and Concas, Maria Pina and Gasparini, Paolo and Boutin, Thibaud and Kolcic, Ivana and Polasek, Ozren and Rudan, Igor and Araujo, Nathalia M and Lima-Costa, Maria Fernanda and Ribeiro, Antonio Luiz P and Souza, Renan P and Tarazona-Santos, Eduardo and Giedraitis, Vilmantas and Ingelsson, Erik and Mahajan, Anubha and Morris, Andrew P and del Greco M, Fabiola and Foco, Luisa and G{\"o}gele, Martin and Hicks, Andrew A and Cook, James P and Lind, Lars and Lindgren, Cecilia M and Sundstr{\"o}m, Johan and Nelson, Christopher P and Riaz, Muhammad B and Samani, Nilesh J and Sinagra, Gianfranco and Ulivi, Sheila and K{\"a}h{\"o}nen, Mika and Mishra, Pashupati P and Mononen, Nina and Nikus, Kjell and Caulfield, Mark J and Dominiczak, Anna and Padmanabhan, Sandosh and Montasser, May E and O{\textquoteright}Connell, Jeff R and Ryan, Kathleen and Shuldiner, Alan R and Aeschbacher, Stefanie and Conen, David and Risch, Lorenz and Th{\'e}riault, S{\'e}bastien and Hutri-K{\"a}h{\"o}nen, Nina and Lehtim{\"a}ki, Terho and Lyytik{\"a}inen, Leo-Pekka and Raitakari, Olli T and Barnes, Catriona L K and Campbell, Harry and Joshi, Peter K and Wilson, James F and Isaacs, Aaron and Kors, Jan A and van Duijn, Cornelia M and Huang, Paul L and Gudnason, Vilmundur and Harris, Tamara B and Launer, Lenore J and Smith, Albert V and Bottinger, Erwin P and Loos, Ruth J F and Nadkarni, Girish N and Preuss, Michael H and Correa, Adolfo and Mei, Hao and Wilson, James and Meitinger, Thomas and M{\"u}ller-Nurasyid, Martina and Peters, Annette and Waldenberger, Melanie and Mangino, Massimo and Spector, Timothy D and Rienstra, Michiel and van de Vegte, Yordi J and van der Harst, Pim and Verweij, Niek and K{\"a}{\"a}b, Stefan and Schramm, Katharina and Sinner, Moritz F and Strauch, Konstantin and Cutler, Michael J and Fatkin, Diane and London, Barry and Olesen, Morten and Roden, Dan M and Benjamin Shoemaker, M and Gustav Smith, J and Biggs, Mary L and Bis, Joshua C and Brody, Jennifer A and Psaty, Bruce M and Rice, Kenneth and Sotoodehnia, Nona and De Grandi, Alessandro and Fuchsberger, Christian and Pattaro, Cristian and Pramstaller, Peter P and Ford, Ian and Wouter Jukema, J and Macfarlane, Peter W and Trompet, Stella and D{\"o}rr, Marcus and Felix, Stephan B and V{\"o}lker, Uwe and Weiss, Stefan and Havulinna, Aki S and Jula, Antti and S{\"a}{\"a}ksj{\"a}rvi, Katri and Salomaa, Veikko and Guo, Xiuqing and Heckbert, Susan R and Lin, Henry J and Rotter, Jerome I and Taylor, Kent D and Yao, Jie and de Mutsert, Ren{\'e}e and Maan, Arie C and Mook-Kanamori, Dennis O and Noordam, Raymond and Cucca, Francesco and Ding, Jun and Lakatta, Edward G and Qian, Yong and Tarasov, Kirill V and Levy, Daniel and Lin, Honghuang and Newton-Cheh, Christopher H and Lunetta, Kathryn L and Murray, Alison D and Porteous, David J and Smith, Blair H and Stricker, Bruno H and Uitterlinden, Andre and van den Berg, Marten E and Haessler, Jeffrey and Jackson, Rebecca D and Kooperberg, Charles and Peters, Ulrike and Reiner, Alexander P and Whitsel, Eric A and Alonso, Alvaro and Arking, Dan E and Boerwinkle, Eric and Ehret, Georg B and Soliman, Elsayed Z and Avery, Christy L and Gogarten, Stephanie M and Kerr, Kathleen F and Laurie, Cathy C and Seyerle, Amanda A and Stilp, Adrienne and Assa, Solmaz and Abdullah Said, M and Yldau van der Ende, M and Lambiase, Pier D and Orini, Michele and Ramirez, Julia and Van Duijvenboden, Stefan and Arnar, David O and Gudbjartsson, Daniel F and Holm, Hilma and Sulem, Patrick and Thorleifsson, Gudmar and Thorolfsdottir, Rosa B and Thorsteinsdottir, Unnur and Benjamin, Emelia J and Tinker, Andrew and Stefansson, Kari and Ellinor, Patrick T and Jamshidi, Yalda and Lubitz, Steven A and Munroe, Patricia B} } @article {8666, title = {Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.}, journal = {Nature}, volume = {590}, year = {2021}, month = {2021 02}, pages = {290-299}, abstract = {

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400~million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400~million detected variants, 97\% have frequencies of less than 1\% and 46\% are singletons that are present in only one individual (53\% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01\%.

}, issn = {1476-4687}, doi = {10.1038/s41586-021-03205-y}, author = {Taliun, Daniel and Harris, Daniel N and Kessler, Michael D and Carlson, Jedidiah and Szpiech, Zachary A and Torres, Raul and Taliun, Sarah A Gagliano and Corvelo, Andr{\'e} and Gogarten, Stephanie M and Kang, Hyun Min and Pitsillides, Achilleas N and LeFaive, Jonathon and Lee, Seung-Been and Tian, Xiaowen and Browning, Brian L and Das, Sayantan and Emde, Anne-Katrin and Clarke, Wayne E and Loesch, Douglas P and Shetty, Amol C and Blackwell, Thomas W and Smith, Albert V and Wong, Quenna and Liu, Xiaoming and Conomos, Matthew P and Bobo, Dean M and Aguet, Francois and Albert, Christine and Alonso, Alvaro and Ardlie, Kristin G and Arking, Dan E and Aslibekyan, Stella and Auer, Paul L and Barnard, John and Barr, R Graham and Barwick, Lucas and Becker, Lewis C and Beer, Rebecca L and Benjamin, Emelia J and Bielak, Lawrence F and Blangero, John and Boehnke, Michael and Bowden, Donald W and Brody, Jennifer A and Burchard, Esteban G and Cade, Brian E and Casella, James F and Chalazan, Brandon and Chasman, Daniel I and Chen, Yii-Der Ida and Cho, Michael H and Choi, Seung Hoan and Chung, Mina K and Clish, Clary B and Correa, Adolfo and Curran, Joanne E and Custer, Brian and Darbar, Dawood and Daya, Michelle and de Andrade, Mariza and DeMeo, Dawn L and Dutcher, Susan K and Ellinor, Patrick T and Emery, Leslie S and Eng, Celeste and Fatkin, Diane and Fingerlin, Tasha and Forer, Lukas and Fornage, Myriam and Franceschini, Nora and Fuchsberger, Christian and Fullerton, Stephanie M and Germer, Soren and Gladwin, Mark T and Gottlieb, Daniel J and Guo, Xiuqing and Hall, Michael E and He, Jiang and Heard-Costa, Nancy L and Heckbert, Susan R and Irvin, Marguerite R and Johnsen, Jill M and Johnson, Andrew D and Kaplan, Robert and Kardia, Sharon L R and Kelly, Tanika and Kelly, Shannon and Kenny, Eimear E and Kiel, Douglas P and Klemmer, Robert and Konkle, Barbara A and Kooperberg, Charles and K{\"o}ttgen, Anna and Lange, Leslie A and Lasky-Su, Jessica and Levy, Daniel and Lin, Xihong and Lin, Keng-Han and Liu, Chunyu and Loos, Ruth J F and Garman, Lori and Gerszten, Robert and Lubitz, Steven A and Lunetta, Kathryn L and Mak, Angel C Y and Manichaikul, Ani and Manning, Alisa K and Mathias, Rasika A and McManus, David D and McGarvey, Stephen T and Meigs, James B and Meyers, Deborah A and Mikulla, Julie L and Minear, Mollie A and Mitchell, Braxton D and Mohanty, Sanghamitra and Montasser, May E and Montgomery, Courtney and Morrison, Alanna C and Murabito, Joanne M and Natale, Andrea and Natarajan, Pradeep and Nelson, Sarah C and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Pankratz, Nathan and Peloso, Gina M and Peyser, Patricia A and Pleiness, Jacob and Post, Wendy S and Psaty, Bruce M and Rao, D C and Redline, Susan and Reiner, Alexander P and Roden, Dan and Rotter, Jerome I and Ruczinski, Ingo and Sarnowski, Chloe and Schoenherr, Sebastian and Schwartz, David A and Seo, Jeong-Sun and Seshadri, Sudha and Sheehan, Vivien A and Sheu, Wayne H and Shoemaker, M Benjamin and Smith, Nicholas L and Smith, Jennifer A and Sotoodehnia, Nona and Stilp, Adrienne M and Tang, Weihong and Taylor, Kent D and Telen, Marilyn and Thornton, Timothy A and Tracy, Russell P and Van Den Berg, David J and Vasan, Ramachandran S and Viaud-Martinez, Karine A and Vrieze, Scott and Weeks, Daniel E and Weir, Bruce S and Weiss, Scott T and Weng, Lu-Chen and Willer, Cristen J and Zhang, Yingze and Zhao, Xutong and Arnett, Donna K and Ashley-Koch, Allison E and Barnes, Kathleen C and Boerwinkle, Eric and Gabriel, Stacey and Gibbs, Richard and Rice, Kenneth M and Rich, Stephen S and Silverman, Edwin K and Qasba, Pankaj and Gan, Weiniu and Papanicolaou, George J and Nickerson, Deborah A and Browning, Sharon R and Zody, Michael C and Z{\"o}llner, Sebastian and Wilson, James G and Cupples, L Adrienne and Laurie, Cathy C and Jaquish, Cashell E and Hernandez, Ryan D and O{\textquoteright}Connor, Timothy D and Abecasis, Goncalo R} } @article {9167, title = {Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes.}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {2022 08 30}, pages = {5106}, abstract = {

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of >= 0.5 times the endophenotype standard deviation nominates up to 35\% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.

}, keywords = {Disease Susceptibility, Endophenotypes, Humans, Long QT Syndrome, Virulence}, issn = {2041-1723}, doi = {10.1038/s41467-022-32009-5}, author = {Halford, Jennifer L and Morrill, Valerie N and Choi, Seung Hoan and Jurgens, Sean J and Melloni, Giorgio and Marston, Nicholas A and Weng, Lu-Chen and Nauffal, Victor and Hall, Amelia W and Gunn, Sophia and Austin-Tse, Christina A and Pirruccello, James P and Khurshid, Shaan and Rehm, Heidi L and Benjamin, Emelia J and Boerwinkle, Eric and Brody, Jennifer A and Correa, Adolfo and Fornwalt, Brandon K and Gupta, Namrata and Haggerty, Christopher M and Harris, Stephanie and Heckbert, Susan R and Hong, Charles C and Kooperberg, Charles and Lin, Henry J and Loos, Ruth J F and Mitchell, Braxton D and Morrison, Alanna C and Post, Wendy and Psaty, Bruce M and Redline, Susan and Rice, Kenneth M and Rich, Stephen S and Rotter, Jerome I and Schnatz, Peter F and Soliman, Elsayed Z and Sotoodehnia, Nona and Wong, Eugene K and Sabatine, Marc S and Ruff, Christian T and Lunetta, Kathryn L and Ellinor, Patrick T and Lubitz, Steven A} } @article {9038, title = {Monogenic and Polygenic Contributions to QTc Prolongation in the Population.}, journal = {Circulation}, year = {2022}, month = {2022 Apr 07}, abstract = {

Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variation to the QT interval in the population. We performed a genome wide association study (GWAS) of the QTc in 84,630 United Kingdom Biobank (UKB) participants and created a polygenic risk score (PRS). Among 26,976 participants with whole genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine (TOPMed) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed. Fifty-four independent loci were identified by GWAS in the UKB. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS comprising 1,110,494 common variants was significantly associated with the QTc in TOPMed (ΔQTc/ = 1.4 ms, 95\% CI 1.3 -1.5; p-value=1.1{\texttimes}10). Carriers of putative pathogenic rare variants had longer QTc than non-carriers (ΔQTc=10.9 ms [7.4-14.4]). 23.7\% of individuals with QTc>480 ms carried either a monogenic rare variant or had a PRS in the top decile (3.4\% monogenic, 21\% top decile of PRS). QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.

}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.121.057261}, author = {Nauffal, Victor and Morrill, Valerie N and Jurgens, Sean J and Choi, Seung Hoan and Hall, Amelia W and Weng, Lu-Chen and Halford, Jennifer L and Austin-Tse, Christina and Haggerty, Christopher M and Harris, Stephanie L and Wong, Eugene K and Alonso, Alvaro and Arking, Dan E and Benjamin, Emelia J and Boerwinkle, Eric and Min, Yuan-I and Correa, Adolfo and Fornwalt, Brandon K and Heckbert, Susan R and Kooperberg, Charles and Lin, Henry J and Loos, Ruth J F and Rice, Kenneth M and Gupta, Namrata and Blackwell, Thomas W and Mitchell, Braxton D and Morrison, Alanna C and Psaty, Bruce M and Post, Wendy S and Redline, Susan and Rehm, Heidi L and Rich, Stephen S and Rotter, Jerome I and Soliman, Elsayed Z and Sotoodehnia, Nona and Lunetta, Kathryn L and Ellinor, Patrick T and Lubitz, Steven A} }