@article {6629, title = {Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.}, journal = {PLoS Genet}, volume = {9}, year = {2013}, month = {2013 Mar}, pages = {e1003379}, abstract = {

Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 {\texttimes} 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74\% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.

}, keywords = {African Americans, Apolipoproteins A, Cholesterol, HDL, Cholesterol, LDL, European Continental Ancestry Group, Genome-Wide Association Study, Humans, Lipoproteins, HDL, Lipoproteins, LDL, Proprotein Convertases, Serine Endopeptidases, Triglycerides}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003379}, author = {Wu, Ying and Waite, Lindsay L and Jackson, Anne U and Sheu, Wayne H-H and Buyske, Steven and Absher, Devin and Arnett, Donna K and Boerwinkle, Eric and Bonnycastle, Lori L and Carty, Cara L and Cheng, Iona and Cochran, Barbara and Croteau-Chonka, Damien C and Dumitrescu, Logan and Eaton, Charles B and Franceschini, Nora and Guo, Xiuqing and Henderson, Brian E and Hindorff, Lucia A and Kim, Eric and Kinnunen, Leena and Komulainen, Pirjo and Lee, Wen-Jane and Le Marchand, Lo{\"\i}c and Lin, Yi and Lindstr{\"o}m, Jaana and Lingaas-Holmen, Oddgeir and Mitchell, Sabrina L and Narisu, Narisu and Robinson, Jennifer G and Schumacher, Fred and Stan{\v c}{\'a}kov{\'a}, Alena and Sundvall, Jouko and Sung, Yun-Ju and Swift, Amy J and Wang, Wen-Chang and Wilkens, Lynne and Wilsgaard, Tom and Young, Alicia M and Adair, Linda S and Ballantyne, Christie M and B{\r u}zkov{\'a}, Petra and Chakravarti, Aravinda and Collins, Francis S and Duggan, David and Feranil, Alan B and Ho, Low-Tone and Hung, Yi-Jen and Hunt, Steven C and Hveem, Kristian and Juang, Jyh-Ming J and Kes{\"a}niemi, Antero Y and Kuusisto, Johanna and Laakso, Markku and Lakka, Timo A and Lee, I-Te and Leppert, Mark F and Matise, Tara C and Moilanen, Leena and Nj{\o}lstad, Inger and Peters, Ulrike and Quertermous, Thomas and Rauramaa, Rainer and Rotter, Jerome I and Saramies, Jouko and Tuomilehto, Jaakko and Uusitupa, Matti and Wang, Tzung-Dau and Boehnke, Michael and Haiman, Christopher A and Chen, Yii-der I and Kooperberg, Charles and Assimes, Themistocles L and Crawford, Dana C and Hsiung, Chao A and North, Kari E and Mohlke, Karen L} } @article {6686, title = {Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.}, journal = {Nat Commun}, volume = {6}, year = {2015}, month = {2015}, pages = {5897}, abstract = {

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4\%) with lower FG (β=-0.09{\textpm}0.01 mmol l(-1), P=3.4 {\texttimes} 10(-12)), T2D risk (OR[95\%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07{\textpm}0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16{\textpm}0.05 mmol l(-1), P=4.3 {\texttimes} 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 {\texttimes} 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20\%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02{\textpm}0.004 mmol l(-1), P=1.3 {\texttimes} 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

}, keywords = {African Continental Ancestry Group, Blood Glucose, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Exome, Fasting, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Glucagon-Like Peptide-1 Receptor, Glucose-6-Phosphatase, Humans, Insulin, Mutation Rate, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide}, issn = {2041-1723}, doi = {10.1038/ncomms6897}, author = {Wessel, Jennifer and Chu, Audrey Y and Willems, Sara M and Wang, Shuai and Yaghootkar, Hanieh and Brody, Jennifer A and Dauriz, Marco and Hivert, Marie-France and Raghavan, Sridharan and Lipovich, Leonard and Hidalgo, Bertha and Fox, Keolu and Huffman, Jennifer E and An, Ping and Lu, Yingchang and Rasmussen-Torvik, Laura J and Grarup, Niels and Ehm, Margaret G and Li, Li and Baldridge, Abigail S and Stan{\v c}{\'a}kov{\'a}, Alena and Abrol, Ravinder and Besse, C{\'e}line and Boland, Anne and Bork-Jensen, Jette and Fornage, Myriam and Freitag, Daniel F and Garcia, Melissa E and Guo, Xiuqing and Hara, Kazuo and Isaacs, Aaron and Jakobsdottir, Johanna and Lange, Leslie A and Layton, Jill C and Li, Man and Hua Zhao, Jing and Meidtner, Karina and Morrison, Alanna C and Nalls, Mike A and Peters, Marjolein J and Sabater-Lleal, Maria and Schurmann, Claudia and Silveira, Angela and Smith, Albert V and Southam, Lorraine and Stoiber, Marcus H and Strawbridge, Rona J and Taylor, Kent D and Varga, Tibor V and Allin, Kristine H and Amin, Najaf and Aponte, Jennifer L and Aung, Tin and Barbieri, Caterina and Bihlmeyer, Nathan A and Boehnke, Michael and Bombieri, Cristina and Bowden, Donald W and Burns, Sean M and Chen, Yuning and Chen, Yii-DerI and Cheng, Ching-Yu and Correa, Adolfo and Czajkowski, Jacek and Dehghan, Abbas and Ehret, Georg B and Eiriksdottir, Gudny and Escher, Stefan A and Farmaki, Aliki-Eleni and Fr{\r a}nberg, Mattias and Gambaro, Giovanni and Giulianini, Franco and Goddard, William A and Goel, Anuj and Gottesman, Omri and Grove, Megan L and Gustafsson, Stefan and Hai, Yang and Hallmans, G{\"o}ran and Heo, Jiyoung and Hoffmann, Per and Ikram, Mohammad K and Jensen, Richard A and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and Karaleftheri, Maria and Khor, Chiea C and Kirkpatrick, Andrea and Kraja, Aldi T and Kuusisto, Johanna and Lange, Ethan M and Lee, I T and Lee, Wen-Jane and Leong, Aaron and Liao, Jiemin and Liu, Chunyu and Liu, Yongmei and Lindgren, Cecilia M and Linneberg, Allan and Malerba, Giovanni and Mamakou, Vasiliki and Marouli, Eirini and Maruthur, Nisa M and Matchan, Angela and McKean-Cowdin, Roberta and McLeod, Olga and Metcalf, Ginger A and Mohlke, Karen L and Muzny, Donna M and Ntalla, Ioanna and Palmer, Nicholette D and Pasko, Dorota and Peter, Andreas and Rayner, Nigel W and Renstrom, Frida and Rice, Ken and Sala, Cinzia F and Sennblad, Bengt and Serafetinidis, Ioannis and Smith, Jennifer A and Soranzo, Nicole and Speliotes, Elizabeth K and Stahl, Eli A and Stirrups, Kathleen and Tentolouris, Nikos and Thanopoulou, Anastasia and Torres, Mina and Traglia, Michela and Tsafantakis, Emmanouil and Javad, Sundas and Yanek, Lisa R and Zengini, Eleni and Becker, Diane M and Bis, Joshua C and Brown, James B and Cupples, L Adrienne and Hansen, Torben and Ingelsson, Erik and Karter, Andrew J and Lorenzo, Carlos and Mathias, Rasika A and Norris, Jill M and Peloso, Gina M and Sheu, Wayne H-H and Toniolo, Daniela and Vaidya, Dhananjay and Varma, Rohit and Wagenknecht, Lynne E and Boeing, Heiner and Bottinger, Erwin P and Dedoussis, George and Deloukas, Panos and Ferrannini, Ele and Franco, Oscar H and Franks, Paul W and Gibbs, Richard A and Gudnason, Vilmundur and Hamsten, Anders and Harris, Tamara B and Hattersley, Andrew T and Hayward, Caroline and Hofman, Albert and Jansson, Jan-H{\r a}kan and Langenberg, Claudia and Launer, Lenore J and Levy, Daniel and Oostra, Ben A and O{\textquoteright}Donnell, Christopher J and O{\textquoteright}Rahilly, Stephen and Padmanabhan, Sandosh and Pankow, James S and Polasek, Ozren and Province, Michael A and Rich, Stephen S and Ridker, Paul M and Rudan, Igor and Schulze, Matthias B and Smith, Blair H and Uitterlinden, Andr{\'e} G and Walker, Mark and Watkins, Hugh and Wong, Tien Y and Zeggini, Eleftheria and Laakso, Markku and Borecki, Ingrid B and Chasman, Daniel I and Pedersen, Oluf and Psaty, Bruce M and Tai, E Shyong and van Duijn, Cornelia M and Wareham, Nicholas J and Waterworth, Dawn M and Boerwinkle, Eric and Kao, W H Linda and Florez, Jose C and Loos, Ruth J F and Wilson, James G and Frayling, Timothy M and Siscovick, David S and Dupuis, Jos{\'e}e and Rotter, Jerome I and Meigs, James B and Scott, Robert A and Goodarzi, Mark O} } @article {7264, title = {Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.}, journal = {Nat Genet}, volume = {48}, year = {2016}, month = {2016 Oct}, pages = {1162-70}, abstract = {

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

}, issn = {1546-1718}, doi = {10.1038/ng.3660}, author = {Liu, Chunyu and Kraja, Aldi T and Smith, Jennifer A and Brody, Jennifer A and Franceschini, Nora and Bis, Joshua C and Rice, Kenneth and Morrison, Alanna C and Lu, Yingchang and Weiss, Stefan and Guo, Xiuqing and Palmas, Walter and Martin, Lisa W and Chen, Yii-Der Ida and Surendran, Praveen and Drenos, Fotios and Cook, James P and Auer, Paul L and Chu, Audrey Y and Giri, Ayush and Zhao, Wei and Jakobsdottir, Johanna and Lin, Li-An and Stafford, Jeanette M and Amin, Najaf and Mei, Hao and Yao, Jie and Voorman, Arend and Larson, Martin G and Grove, Megan L and Smith, Albert V and Hwang, Shih-Jen and Chen, Han and Huan, Tianxiao and Kosova, Gulum and Stitziel, Nathan O and Kathiresan, Sekar and Samani, Nilesh and Schunkert, Heribert and Deloukas, Panos and Li, Man and Fuchsberger, Christian and Pattaro, Cristian and Gorski, Mathias and Kooperberg, Charles and Papanicolaou, George J and Rossouw, Jacques E and Faul, Jessica D and Kardia, Sharon L R and Bouchard, Claude and Raffel, Leslie J and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Vasan, Ramachandran S and O{\textquoteright}Donnell, Christopher J and Taylor, Kent D and Liu, Kiang and Bottinger, Erwin P and Gottesman, Omri and Daw, E Warwick and Giulianini, Franco and Ganesh, Santhi and Salfati, Elias and Harris, Tamara B and Launer, Lenore J and D{\"o}rr, Marcus and Felix, Stephan B and Rettig, Rainer and V{\"o}lzke, Henry and Kim, Eric and Lee, Wen-Jane and Lee, I-Te and Sheu, Wayne H-H and Tsosie, Krystal S and Edwards, Digna R Velez and Liu, Yongmei and Correa, Adolfo and Weir, David R and V{\"o}lker, Uwe and Ridker, Paul M and Boerwinkle, Eric and Gudnason, Vilmundur and Reiner, Alexander P and van Duijn, Cornelia M and Borecki, Ingrid B and Edwards, Todd L and Chakravarti, Aravinda and Rotter, Jerome I and Psaty, Bruce M and Loos, Ruth J F and Fornage, Myriam and Ehret, Georg B and Newton-Cheh, Christopher and Levy, Daniel and Chasman, Daniel I} } @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 {7571, title = {Genome-Wide Association Study Meta-Analysis of Long-Term Average Blood Pressure in East Asians.}, journal = {Circ Cardiovasc Genet}, volume = {10}, year = {2017}, month = {2017 Apr}, pages = {e001527}, abstract = {

BACKGROUND: Genome-wide single marker and gene-based meta-analyses of long-term average (LTA) blood pressure (BP) phenotypes may reveal novel findings for BP.

METHODS AND RESULTS: We conducted genome-wide analysis among 18 422 East Asian participants (stage 1) followed by replication study of <=46 629 participants of European ancestry (stage 2). Significant single-nucleotide polymorphisms and genes were determined by a P<5.0{\texttimes}10-8 and 2.5{\texttimes}10-6, respectively, in joint analyses of stage-1 and stage-2 data. We identified 1 novel ARL3 variant, rs4919669 at 10q24.32, influencing LTA systolic BP (stage-1 P=5.03{\texttimes}10-8, stage-2 P=8.64{\texttimes}10-3, joint P=2.63{\texttimes}10-8) and mean arterial pressure (stage-1 P=3.59{\texttimes}10-9, stage-2 P=2.35{\texttimes}10-2, joint P=2.64{\texttimes}10-8). Three previously reported BP loci (WBP1L, NT5C2, and ATP2B1) were also identified for all BP phenotypes. Gene-based analysis provided the first robust evidence for association of KCNJ11 with LTA systolic BP (stage-1 P=8.55{\texttimes}10-6, stage-2 P=1.62{\texttimes}10-5, joint P=3.28{\texttimes}10-9) and mean arterial pressure (stage-1 P=9.19{\texttimes}10-7, stage-2 P=9.69{\texttimes}10-5, joint P=2.15{\texttimes}10-9) phenotypes. Fourteen genes (TMEM180, ACTR1A, SUFU, ARL3, SFXN2, WBP1L, CYP17A1, C10orf32, C10orf32-ASMT, AS3MT, CNNM2, and NT5C2 at 10q24.32; ATP2B1 at 12q21.33; and NCR3LG1 at 11p15.1) implicated by previous genome-wide association study meta-analyses were also identified. Among the loci identified by the previous genome-wide association study meta-analysis of LTA BP, we transethnically replicated associations of the KCNK3 marker rs1275988 at 2p23.3 with LTA systolic BP and mean arterial pressure phenotypes (P=1.27{\texttimes}10-4 and 3.30{\texttimes}10-4, respectively).

CONCLUSIONS: We identified 1 novel variant and 1 novel gene and present the first direct evidence of relevance of the KCNK3 locus for LTA BP among East Asians.

}, keywords = {Asian Continental Ancestry Group, Blood Pressure, Far East, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Phenotype, Polymorphism, Single Nucleotide}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.116.001527}, author = {Li, Changwei and Kim, Yun Kyoung and Dorajoo, Rajkumar and Li, Huaixing and Lee, I-Te and Cheng, Ching-Yu and He, Meian and Sheu, Wayne H-H and Guo, Xiuqing and Ganesh, Santhi K and He, Jiang and Lee, Juyoung and Liu, Jianjun and Hu, Yao and Rao, Dabeeru C and Tsai, Fuu-Jen and Koh, Jia Yu and Hu, Hua and Liang, Kae-Woei and Palmas, Walter and Hixson, James E and Han, Sohee and Teo, Yik-Ying and Wang, Yiqin and Chen, Jing and Lu, Chieh Hsiang and Zheng, Yingfeng and Gui, Lixuan and Lee, Wen-Jane and Yao, Jie and Gu, Dongfeng and Han, Bok-Ghee and Sim, Xueling and Sun, Liang and Zhao, Jinying and Chen, Chien-Hsiun and Kumari, Neelam and He, Yunfeng and Taylor, Kent D and Raffel, Leslie J and Moon, Sanghoon and Rotter, Jerome I and Ida Chen, Yii-Der and Wu, Tangchun and Wong, Tien Yin and Wu, Jer-Yuarn and Lin, Xu and Tai, E-Shyong and Kim, Bong-Jo and Kelly, Tanika N} } @article {7596, title = {Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.}, journal = {PLoS Med}, volume = {14}, year = {2017}, month = {2017 Sep}, pages = {e1002383}, abstract = {

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

METHODS \& FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95\% CI 1.04-1.06, per HbA1c-raising allele, p = 3 {\texttimes} 10-29); whereas GS-E was not (OR = 1.00, 95\% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11\%) was associated with an absolute decrease in HbA1c of 0.81\%-units (95\% CI 0.66-0.96) per allele in hemizygous men, and 0.68\%-units (95\% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2\% (N = 0.65 million, 95\% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.

CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

}, keywords = {Diabetes Mellitus, Type 2, Genetic Variation, Genome-Wide Association Study, Glycated Hemoglobin A, Humans, Phenotype, Risk}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1002383}, author = {Wheeler, Eleanor and Leong, Aaron and Liu, Ching-Ti and Hivert, Marie-France and Strawbridge, Rona J and Podmore, Clara and Li, Man and Yao, Jie and Sim, Xueling and Hong, Jaeyoung and Chu, Audrey Y and Zhang, Weihua and Wang, Xu and Chen, Peng and Maruthur, Nisa M and Porneala, Bianca C and Sharp, Stephen J and Jia, Yucheng and Kabagambe, Edmond K and Chang, Li-Ching and Chen, Wei-Min and Elks, Cathy E and Evans, Daniel S and Fan, Qiao and Giulianini, Franco and Go, Min Jin and Hottenga, Jouke-Jan and Hu, Yao and Jackson, Anne U and Kanoni, Stavroula and Kim, Young Jin and Kleber, Marcus E and Ladenvall, Claes and Lecoeur, C{\'e}cile and Lim, Sing-Hui and Lu, Yingchang and Mahajan, Anubha and Marzi, Carola and Nalls, Mike A and Navarro, Pau and Nolte, Ilja M and Rose, Lynda M and Rybin, Denis V and Sanna, Serena and Shi, Yuan and Stram, Daniel O and Takeuchi, Fumihiko and Tan, Shu Pei and van der Most, Peter J and van Vliet-Ostaptchouk, Jana V and Wong, Andrew and Yengo, Loic and Zhao, Wanting and Goel, Anuj and Martinez Larrad, Maria Teresa and Radke, D{\"o}rte and Salo, Perttu and Tanaka, Toshiko and van Iperen, Erik P A and Abecasis, Goncalo and Afaq, Saima and Alizadeh, Behrooz Z and Bertoni, Alain G and Bonnefond, Am{\'e}lie and B{\"o}ttcher, Yvonne and Bottinger, Erwin P and Campbell, Harry and Carlson, Olga D and Chen, Chien-Hsiun and Cho, Yoon Shin and Garvey, W Timothy and Gieger, Christian and Goodarzi, Mark O and Grallert, Harald and Hamsten, Anders and Hartman, Catharina A and Herder, Christian and Hsiung, Chao Agnes and Huang, Jie and Igase, Michiya and Isono, Masato and Katsuya, Tomohiro and Khor, Chiea-Chuen and Kiess, Wieland and Kohara, Katsuhiko and Kovacs, Peter and Lee, Juyoung and Lee, Wen-Jane and Lehne, Benjamin and Li, Huaixing and Liu, Jianjun and Lobbens, Stephane and Luan, Jian{\textquoteright}an and Lyssenko, Valeriya and Meitinger, Thomas and Miki, Tetsuro and Miljkovic, Iva and Moon, Sanghoon and Mulas, Antonella and M{\"u}ller, Gabriele and M{\"u}ller-Nurasyid, Martina and Nagaraja, Ramaiah and Nauck, Matthias and Pankow, James S and Polasek, Ozren and Prokopenko, Inga and Ramos, Paula S and Rasmussen-Torvik, Laura and Rathmann, Wolfgang and Rich, Stephen S and Robertson, Neil R and Roden, Michael and Roussel, Ronan and Rudan, Igor and Scott, Robert A and Scott, William R and Sennblad, Bengt and Siscovick, David S and Strauch, Konstantin and Sun, Liang and Swertz, Morris and Tajuddin, Salman M and Taylor, Kent D and Teo, Yik-Ying and Tham, Yih Chung and T{\"o}njes, Anke and Wareham, Nicholas J and Willemsen, Gonneke and Wilsgaard, Tom and Hingorani, Aroon D and Egan, Josephine and Ferrucci, Luigi and Hovingh, G Kees and Jula, Antti and Kivimaki, Mika and Kumari, Meena and Nj{\o}lstad, Inger and Palmer, Colin N A and Serrano R{\'\i}os, Manuel and Stumvoll, Michael and Watkins, Hugh and Aung, Tin and Bl{\"u}her, Matthias and Boehnke, Michael and Boomsma, Dorret I and Bornstein, Stefan R and Chambers, John C and Chasman, Daniel I and Chen, Yii-Der Ida and Chen, Yduan-Tsong and Cheng, Ching-Yu and Cucca, Francesco and de Geus, Eco J C and Deloukas, Panos and Evans, Michele K and Fornage, Myriam and Friedlander, Yechiel and Froguel, Philippe and Groop, Leif and Gross, Myron D and Harris, Tamara B and Hayward, Caroline and Heng, Chew-Kiat and Ingelsson, Erik and Kato, Norihiro and Kim, Bong-Jo and Koh, Woon-Puay and Kooner, Jaspal S and K{\"o}rner, Antje and Kuh, Diana and Kuusisto, Johanna and Laakso, Markku and Lin, Xu and Liu, Yongmei and Loos, Ruth J F and Magnusson, Patrik K E and M{\"a}rz, Winfried and McCarthy, Mark I and Oldehinkel, Albertine J and Ong, Ken K and Pedersen, Nancy L and Pereira, Mark A and Peters, Annette and Ridker, Paul M and Sabanayagam, Charumathi and Sale, Michele and Saleheen, Danish and Saltevo, Juha and Schwarz, Peter Eh and Sheu, Wayne H H and Snieder, Harold and Spector, Timothy D and Tabara, Yasuharu and Tuomilehto, Jaakko and van Dam, Rob M and Wilson, James G and Wilson, James F and Wolffenbuttel, Bruce H R and Wong, Tien Yin and Wu, Jer-Yuarn and Yuan, Jian-Min and Zonderman, Alan B and Soranzo, Nicole and Guo, Xiuqing and Roberts, David J and Florez, Jose C and Sladek, Robert and Dupuis, Jos{\'e}e and Morris, Andrew P and Tai, E-Shyong and Selvin, Elizabeth and Rotter, Jerome I and Langenberg, Claudia and Barroso, In{\^e}s and Meigs, James B} } @article {7465, title = {Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci.}, journal = {Hum Genet}, volume = {136}, year = {2017}, month = {2017 Jun}, pages = {771-800}, abstract = {

Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70~kg/m(2)) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p~<~0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.

}, keywords = {Body Mass Index, Ethnic Groups, Genetics, Population, Humans, Obesity}, issn = {1432-1203}, doi = {10.1007/s00439-017-1787-6}, author = {Fernandez-Rhodes, Lindsay and Gong, Jian and Haessler, Jeffrey and Franceschini, Nora and Graff, Mariaelisa and Nishimura, Katherine K and Wang, Yujie and Highland, Heather M and Yoneyama, Sachiko and Bush, William S and Goodloe, Robert and Ritchie, Marylyn D and Crawford, Dana and Gross, Myron and Fornage, Myriam and B{\r u}zkov{\'a}, Petra and Tao, Ran and Isasi, Carmen and Avil{\'e}s-Santa, Larissa and Daviglus, Martha and Mackey, Rachel H and Houston, Denise and Gu, C Charles and Ehret, Georg and Nguyen, Khanh-Dung H and Lewis, Cora E and Leppert, Mark and Irvin, Marguerite R and Lim, Unhee and Haiman, Christopher A and Le Marchand, Lo{\"\i}c and Schumacher, Fredrick and Wilkens, Lynne and Lu, Yingchang and Bottinger, Erwin P and Loos, Ruth J L and Sheu, Wayne H-H and Guo, Xiuqing and Lee, Wen-Jane and Hai, Yang and Hung, Yi-Jen and Absher, Devin and Wu, I-Chien and Taylor, Kent D and Lee, I-Te and Liu, Yeheng and Wang, Tzung-Dau and Quertermous, Thomas and Juang, Jyh-Ming J and Rotter, Jerome I and Assimes, Themistocles and Hsiung, Chao A and Chen, Yii-Der Ida and Prentice, Ross and Kuller, Lewis H and Manson, JoAnn E and Kooperberg, Charles and Smokowski, Paul and Robinson, Whitney R and Gordon-Larsen, Penny and Li, Rongling and Hindorff, Lucia and Buyske, Steven and Matise, Tara C and Peters, Ulrike and North, Kari E} } @article {7686, title = {A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 Mar 01}, pages = {375-400}, abstract = {

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined \~{}18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5~{\texttimes} 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5~{\texttimes} 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.01.015}, author = {Sung, Yun J and Winkler, Thomas W and de Las Fuentes, Lisa and Bentley, Amy R and Brown, Michael R and Kraja, Aldi T and Schwander, Karen and Ntalla, Ioanna and Guo, Xiuqing and Franceschini, Nora and Lu, Yingchang and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Marten, Jonathan and Musani, Solomon K and Li, Changwei and Feitosa, Mary F and Kilpel{\"a}inen, Tuomas O and Richard, Melissa A and Noordam, Raymond and Aslibekyan, Stella and Aschard, Hugues and Bartz, Traci M and Dorajoo, Rajkumar and Liu, Yongmei and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert Vernon and Tajuddin, Salman M and Tayo, Bamidele O and Warren, Helen R and Zhao, Wei and Zhou, Yanhua and Matoba, Nana and Sofer, Tamar and Alver, Maris and Amini, Marzyeh and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Gandin, Ilaria and Gao, Chuan and Giulianini, Franco and Goel, Anuj and Harris, Sarah E and Hartwig, Fernando Pires and Horimoto, Andrea R V R and Hsu, Fang-Chi and Jackson, Anne U and K{\"a}h{\"o}nen, Mika and Kasturiratne, Anuradhani and Kuhnel, Brigitte and Leander, Karin and Lee, Wen-Jane and Lin, Keng-Hung and {\textquoteright}an Luan, Jian and McKenzie, Colin A and Meian, He and Nelson, Christopher P and Rauramaa, Rainer and Schupf, Nicole and Scott, Robert A and Sheu, Wayne H H and Stan{\v c}{\'a}kov{\'a}, Alena and Takeuchi, Fumihiko and van der Most, Peter J and Varga, Tibor V and Wang, Heming and Wang, Yajuan and Ware, Erin B and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Zhang, Weihua and Zhao, Jing Hua and Afaq, Saima and Alfred, Tamuno and Amin, Najaf and Arking, Dan and Aung, Tin and Barr, R Graham and Bielak, Lawrence F and Boerwinkle, Eric and Bottinger, Erwin P and Braund, Peter S and Brody, Jennifer A and Broeckel, Ulrich and Cabrera, Claudia P and Cade, Brian and Caizheng, Yu and Campbell, Archie and Canouil, Micka{\"e}l and Chakravarti, Aravinda and Chauhan, Ganesh and Christensen, Kaare and Cocca, Massimiliano and Collins, Francis S and Connell, John M and de Mutsert, Ren{\'e}e and de Silva, H Janaka and Debette, Stephanie and D{\"o}rr, Marcus and Duan, Qing and Eaton, Charles B and Ehret, Georg and Evangelou, Evangelos and Faul, Jessica D and Fisher, Virginia A and Forouhi, Nita G and Franco, Oscar H and Friedlander, Yechiel and Gao, He and Gigante, Bruna and Graff, Misa and Gu, C Charles and Gu, Dongfeng and Gupta, Preeti and Hagenaars, Saskia P and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Hofman, Albert and Howard, Barbara V and Hunt, Steven and Irvin, Marguerite R and Jia, Yucheng and Joehanes, Roby and Justice, Anne E and Katsuya, Tomohiro and Kaufman, Joel and Kerrison, Nicola D and Khor, Chiea Chuen and Koh, Woon-Puay and Koistinen, Heikki A and Komulainen, Pirjo and Kooperberg, Charles and Krieger, Jose E and Kubo, Michiaki and Kuusisto, Johanna and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lehne, Benjamin and Lewis, Cora E and Li, Yize and Lim, Sing Hui and Lin, Shiow and Liu, Ching-Ti and Liu, Jianjun and Liu, Jingmin and Liu, Kiang and Liu, Yeheng and Loh, Marie and Lohman, Kurt K and Long, Jirong and Louie, Tin and M{\"a}gi, Reedik and Mahajan, Anubha and Meitinger, Thomas and Metspalu, Andres and Milani, Lili and Momozawa, Yukihide and Morris, Andrew P and Mosley, Thomas H and Munson, Peter and Murray, Alison D and Nalls, Mike A and Nasri, Ubaydah and Norris, Jill M and North, Kari and Ogunniyi, Adesola and Padmanabhan, Sandosh and Palmas, Walter R and Palmer, Nicholette D and Pankow, James S and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Raitakari, Olli T and Renstrom, Frida and Rice, Treva K and Ridker, Paul M and Robino, Antonietta and Robinson, Jennifer G and Rose, Lynda M and Rudan, Igor and Sabanayagam, Charumathi and Salako, Babatunde L and Sandow, Kevin and Schmidt, Carsten O and Schreiner, Pamela J and Scott, William R and Seshadri, Sudha and Sever, Peter and Sitlani, Colleen M and Smith, Jennifer A and Snieder, Harold and Starr, John M and Strauch, Konstantin and Tang, Hua and Taylor, Kent D and Teo, Yik Ying and Tham, Yih Chung and Uitterlinden, Andr{\'e} G and Waldenberger, Melanie and Wang, Lihua and Wang, Ya X and Wei, Wen Bin and Williams, Christine and Wilson, Gregory and Wojczynski, Mary K and Yao, Jie and Yuan, Jian-Min and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and Chambers, John C and Chen, Yii-Der Ida and de Faire, Ulf and Deary, Ian J and Esko, T{\~o}nu and Farrall, Martin and Forrester, Terrence and Franks, Paul W and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Horta, Bernardo Lessa and Hung, Yi-Jen and Jonas, Jost B and Kato, Norihiro and Kooner, Jaspal S and Laakso, Markku and Lehtim{\"a}ki, Terho and Liang, Kae-Woei and Magnusson, Patrik K E and Newman, Anne B and Oldehinkel, Albertine J and Pereira, Alexandre C and Redline, Susan and Rettig, Rainer and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Wu, Tangchun and Zheng, Wei and Kamatani, Yoichiro and Laurie, Cathy C and Bouchard, Claude and Cooper, Richard S and Evans, Michele K and Gudnason, Vilmundur and Kardia, Sharon L R and Kritchevsky, Stephen B and Levy, Daniel and O{\textquoteright}Connell, Jeff R and Psaty, Bruce M and van Dam, Rob M and Sims, Mario and Arnett, Donna K and Mook-Kanamori, Dennis O and Kelly, Tanika N and Fox, Ervin R and Hayward, Caroline and Fornage, Myriam and Rotimi, Charles N and Province, Michael A and van Duijn, Cornelia M and Tai, E Shyong and Wong, Tien Yin and Loos, Ruth J F and Reiner, Alex P and Rotter, Jerome I and Zhu, Xiaofeng and Bierut, Laura J and Gauderman, W James and Caulfield, Mark J and Elliott, Paul and Rice, Kenneth and Munroe, Patricia B and Morrison, Alanna C and Cupples, L Adrienne and Rao, Dabeeru C and Chasman, Daniel I} } @article {8198, title = {Associations of autozygosity with a broad range of human phenotypes.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 Oct 31}, pages = {4957}, abstract = {

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55\% decrease [95\% CI 44-66\%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.

}, issn = {2041-1723}, doi = {10.1038/s41467-019-12283-6}, author = {Clark, David W and Okada, Yukinori and Moore, Kristjan H S and Mason, Dan and Pirastu, Nicola and Gandin, Ilaria and Mattsson, Hannele and Barnes, Catriona L K and Lin, Kuang and Zhao, Jing Hua and Deelen, Patrick and Rohde, Rebecca and Schurmann, Claudia and Guo, Xiuqing and Giulianini, Franco and Zhang, Weihua and Medina-G{\'o}mez, Carolina and Karlsson, Robert and Bao, Yanchun and Bartz, Traci M and Baumbach, Clemens and Biino, Ginevra and Bixley, Matthew J and Brumat, Marco and Chai, Jin-Fang and Corre, Tanguy and Cousminer, Diana L and Dekker, Annelot M and Eccles, David A and van Eijk, Kristel R and Fuchsberger, Christian and Gao, He and Germain, Marine and Gordon, Scott D and de Haan, Hugoline G and Harris, Sarah E and Hofer, Edith and Huerta-Chagoya, Alicia and Igartua, Catherine and Jansen, Iris E and Jia, Yucheng and Kacprowski, Tim and Karlsson, Torgny and Kleber, Marcus E and Li, Shengchao Alfred and Li-Gao, Ruifang and Mahajan, Anubha and Matsuda, Koichi and Meidtner, Karina and Meng, Weihua and Montasser, May E and van der Most, Peter J and Munz, Matthias and Nutile, Teresa and Palviainen, Teemu and Prasad, Gauri and Prasad, Rashmi B and Priyanka, Tallapragada Divya Sri and Rizzi, Federica and Salvi, Erika and Sapkota, Bishwa R and Shriner, Daniel and Skotte, Line and Smart, Melissa C and Smith, Albert Vernon and van der Spek, Ashley and Spracklen, Cassandra N and Strawbridge, Rona J and Tajuddin, Salman M and Trompet, Stella and Turman, Constance and Verweij, Niek and Viberti, Clara and Wang, Lihua and Warren, Helen R and Wootton, Robyn E and Yanek, Lisa R and Yao, Jie and Yousri, Noha A and Zhao, Wei and Adeyemo, Adebowale A and Afaq, Saima and Aguilar-Salinas, Carlos Alberto and Akiyama, Masato and Albert, Matthew L and Allison, Matthew A and Alver, Maris and Aung, Tin and Azizi, Fereidoun and Bentley, Amy R and Boeing, Heiner and Boerwinkle, Eric and Borja, Judith B and de Borst, Gert J and Bottinger, Erwin P and Broer, Linda and Campbell, Harry and Chanock, Stephen and Chee, Miao-Li and Chen, Guanjie and Chen, Yii-der I and Chen, Zhengming and Chiu, Yen-Feng and Cocca, Massimiliano and Collins, Francis S and Concas, Maria Pina and Corley, Janie and Cugliari, Giovanni and van Dam, Rob M and Damulina, Anna and Daneshpour, Maryam S and Day, Felix R and Delgado, Graciela E and Dhana, Klodian and Doney, Alexander S F and D{\"o}rr, Marcus and Doumatey, Ayo P and Dzimiri, Nduna and Ebenesersd{\'o}ttir, S Sunna and Elliott, Joshua and Elliott, Paul and Ewert, Ralf and Felix, Janine F and Fischer, Krista and Freedman, Barry I and Girotto, Giorgia and Goel, Anuj and G{\"o}gele, Martin and Goodarzi, Mark O and Graff, Mariaelisa and Granot-Hershkovitz, Einat and Grodstein, Francine and Guarrera, Simonetta and Gudbjartsson, Daniel F and Guity, Kamran and Gunnarsson, Bjarni and Guo, Yu and Hagenaars, Saskia P and Haiman, Christopher A and Halevy, Avner and Harris, Tamara B and Hedayati, Mehdi and van Heel, David A and Hirata, Makoto and H{\"o}fer, Imo and Hsiung, Chao Agnes and Huang, Jinyan and Hung, Yi-Jen and Ikram, M Arfan and Jagadeesan, Anuradha and Jousilahti, Pekka and Kamatani, Yoichiro and Kanai, Masahiro and Kerrison, Nicola D and Kessler, Thorsten and Khaw, Kay-Tee and Khor, Chiea Chuen and de Kleijn, Dominique P V and Koh, Woon-Puay and Kolcic, Ivana and Kraft, Peter and Kr{\"a}mer, Bernhard K and Kutalik, Zolt{\'a}n and Kuusisto, Johanna and Langenberg, Claudia and Launer, Lenore J and Lawlor, Deborah A and Lee, I-Te and Lee, Wen-Jane and Lerch, Markus M and Li, Liming and Liu, Jianjun and Loh, Marie and London, Stephanie J and Loomis, Stephanie and Lu, Yingchang and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Manichaikul, Ani W and Manunta, Paolo and M{\'a}sson, G{\'\i}sli and Matoba, Nana and Mei, Xue W and Meisinger, Christa and Meitinger, Thomas and Mezzavilla, Massimo and Milani, Lili and Millwood, Iona Y and Momozawa, Yukihide and Moore, Amy and Morange, Pierre-Emmanuel and Moreno-Macias, Hortensia and Mori, Trevor A and Morrison, Alanna C and Muka, Taulant and Murakami, Yoshinori and Murray, Alison D and de Mutsert, Ren{\'e}e and Mychaleckyj, Josyf C and Nalls, Mike A and Nauck, Matthias and Neville, Matt J and Nolte, Ilja M and Ong, Ken K and Orozco, Lorena and Padmanabhan, Sandosh and P{\'a}lsson, Gunnar and Pankow, James S and Pattaro, Cristian and Pattie, Alison and Polasek, Ozren and Poulter, Neil and Pramstaller, Peter P and Quintana-Murci, Lluis and R{\"a}ikk{\"o}nen, Katri and Ralhan, Sarju and Rao, Dabeeru C and van Rheenen, Wouter and Rich, Stephen S and Ridker, Paul M and Rietveld, Cornelius A and Robino, Antonietta and van Rooij, Frank J A and Ruggiero, Daniela and Saba, Yasaman and Sabanayagam, Charumathi and Sabater-Lleal, Maria and Sala, Cinzia Felicita and Salomaa, Veikko and Sandow, Kevin and Schmidt, Helena and Scott, Laura J and Scott, William R and Sedaghati-Khayat, Bahareh and Sennblad, Bengt and van Setten, Jessica and Sever, Peter J and Sheu, Wayne H-H and Shi, Yuan and Shrestha, Smeeta and Shukla, Sharvari Rahul and Sigurdsson, Jon K and Sikka, Timo Tonis and Singh, Jai Rup and Smith, Blair H and Stan{\v c}{\'a}kov{\'a}, Alena and Stanton, Alice and Starr, John M and Stefansdottir, Lilja and Straker, Leon and Sulem, Patrick and Sveinbjornsson, Gardar and Swertz, Morris A and Taylor, Adele M and Taylor, Kent D and Terzikhan, Natalie and Tham, Yih-Chung and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tillander, Annika and Tracy, Russell P and Tusi{\'e}-Luna, Teresa and Tzoulaki, Ioanna and Vaccargiu, Simona and Vangipurapu, Jagadish and Veldink, Jan H and Vitart, Veronique and V{\"o}lker, Uwe and Vuoksimaa, Eero and Wakil, Salma M and Waldenberger, Melanie and Wander, Gurpreet S and Wang, Ya Xing and Wareham, Nicholas J and Wild, Sarah and Yajnik, Chittaranjan S and Yuan, Jian-Min and Zeng, Lingyao and Zhang, Liang and Zhou, Jie and Amin, Najaf and Asselbergs, Folkert W and Bakker, Stephan J L and Becker, Diane M and Lehne, Benjamin and Bennett, David A and van den Berg, Leonard H and Berndt, Sonja I and Bharadwaj, Dwaipayan and Bielak, Lawrence F and Bochud, Murielle and Boehnke, Mike and Bouchard, Claude and Bradfield, Jonathan P and Brody, Jennifer A and Campbell, Archie and Carmi, Shai and Caulfield, Mark J and Cesarini, David and Chambers, John C and Chandak, Giriraj Ratan and Cheng, Ching-Yu and Ciullo, Marina and Cornelis, Marilyn and Cusi, Daniele and Smith, George Davey and Deary, Ian J and Dorajoo, Rajkumar and van Duijn, Cornelia M and Ellinghaus, David and Erdmann, Jeanette and Eriksson, Johan G and Evangelou, Evangelos and Evans, Michele K and Faul, Jessica D and Feenstra, Bjarke and Feitosa, Mary and Foisy, Sylvain and Franke, Andre and Friedlander, Yechiel and Gasparini, Paolo and Gieger, Christian and Gonzalez, Clicerio and Goyette, Philippe and Grant, Struan F A and Griffiths, Lyn R and Groop, Leif and Gudnason, Vilmundur and Gyllensten, Ulf and Hakonarson, Hakon and Hamsten, Anders and van der Harst, Pim and Heng, Chew-Kiat and Hicks, Andrew A and Hochner, Hagit and Huikuri, Heikki and Hunt, Steven C and Jaddoe, Vincent W V and De Jager, Philip L and Johannesson, Magnus and Johansson, Asa and Jonas, Jost B and Jukema, J Wouter and Junttila, Juhani and Kaprio, Jaakko and Kardia, Sharon L R and Karpe, Fredrik and Kumari, Meena and Laakso, Markku and van der Laan, Sander W and Lahti, Jari and Laudes, Matthias and Lea, Rodney A and Lieb, Wolfgang and Lumley, Thomas and Martin, Nicholas G and M{\"a}rz, Winfried and Matullo, Giuseppe and McCarthy, Mark I and Medland, Sarah E and Merriman, Tony R and Metspalu, Andres and Meyer, Brian F and Mohlke, Karen L and Montgomery, Grant W and Mook-Kanamori, Dennis and Munroe, Patricia B and North, Kari E and Nyholt, Dale R and O{\textquoteright}Connell, Jeffery R and Ober, Carole and Oldehinkel, Albertine J and Palmas, Walter and Palmer, Colin and Pasterkamp, Gerard G and Patin, Etienne and Pennell, Craig E and Perusse, Louis and Peyser, Patricia A and Pirastu, Mario and Polderman, Tinca J C and Porteous, David J and Posthuma, Danielle and Psaty, Bruce M and Rioux, John D and Rivadeneira, Fernando and Rotimi, Charles and Rotter, Jerome I and Rudan, Igor and den Ruijter, Hester M and Sanghera, Dharambir K and Sattar, Naveed and Schmidt, Reinhold and Schulze, Matthias B and Schunkert, Heribert and Scott, Robert A and Shuldiner, Alan R and Sim, Xueling and Small, Neil and Smith, Jennifer A and Sotoodehnia, Nona and Tai, E-Shyong and Teumer, Alexander and Timpson, Nicholas J and Toniolo, Daniela and Tr{\'e}gou{\"e}t, David-Alexandre and Tuomi, Tiinamaija and Vollenweider, Peter and Wang, Carol A and Weir, David R and Whitfield, John B and Wijmenga, Cisca and Wong, Tien-Yin and Wright, John and Yang, Jingyun and Yu, Lei and Zemel, Babette S and Zonderman, Alan B and Perola, Markus and Magnusson, Patrik K E and Uitterlinden, Andr{\'e} G and Kooner, Jaspal S and Chasman, Daniel I and Loos, Ruth J F and Franceschini, Nora and Franke, Lude and Haley, Chris S and Hayward, Caroline and Walters, Robin G and Perry, John R B and Esko, T{\~o}nu and Helgason, Agnar and Stefansson, Kari and Joshi, Peter K and Kubo, Michiaki and Wilson, James F} } @article {9387, title = {Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.}, journal = {Nature}, volume = {616}, year = {2023}, month = {2023 Apr}, pages = {755-763}, abstract = {

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but~this effect was not seen in~clones with~driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental~knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

}, keywords = {Alleles, Animals, Clonal Hematopoiesis, Genome-Wide Association Study, Hematopoiesis, Hematopoietic Stem Cells, Humans, Mice, Mutation, Promoter Regions, Genetic}, issn = {1476-4687}, doi = {10.1038/s41586-023-05806-1}, author = {Weinstock, Joshua S and Gopakumar, Jayakrishnan and Burugula, Bala Bharathi and Uddin, Md Mesbah and Jahn, Nikolaus and Belk, Julia A and Bouzid, Hind and Daniel, Bence and Miao, Zhuang and Ly, Nghi and Mack, Taralynn M and Luna, Sofia E and Prothro, Katherine P and Mitchell, Shaneice R and Laurie, Cecelia A and Broome, Jai G and Taylor, Kent D and Guo, Xiuqing and Sinner, Moritz F and von Falkenhausen, Aenne S and K{\"a}{\"a}b, Stefan 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 Hou, Lifang and Lloyd-Jones, Donald M and Redline, Susan and Cade, Brian E and Psaty, Bruce M and Bis, Joshua C and Brody, Jennifer A and Silverman, Edwin K and Yun, Jeong H and Qiao, Dandi and Palmer, Nicholette D and Freedman, Barry I and Bowden, Donald W and Cho, Michael H and DeMeo, Dawn L and Vasan, Ramachandran S and Yanek, Lisa R and Becker, Lewis C and Kardia, Sharon L R and Peyser, Patricia A and He, Jiang and Rienstra, Michiel and van der Harst, Pim 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 Cutler, Michael J and Knight, Stacey and Muhlestein, J Brent and Correa, Adolfo and Raffield, Laura M and Gao, Yan and de Andrade, Mariza and Rotter, Jerome I and Rich, Stephen S and Tracy, Russell P and Konkle, Barbara A and Johnsen, Jill M and Wheeler, Marsha M and Smith, J Gustav and Melander, Olle and Nilsson, Peter M and Custer, Brian S and Duggirala, Ravindranath and Curran, Joanne E and Blangero, John and McGarvey, Stephen and Williams, L Keoki and Xiao, Shujie and Yang, Mao and Gu, C Charles and Chen, Yii-Der Ida and Lee, Wen-Jane and Marcus, Gregory M and Kane, John P and Pullinger, Clive R and Shoemaker, M Benjamin and Darbar, Dawood and Roden, Dan M and Albert, Christine and Kooperberg, Charles and Zhou, Ying and Manson, JoAnn E and Desai, Pinkal and Johnson, Andrew D and Mathias, Rasika A and Blackwell, Thomas W and Abecasis, Goncalo R and Smith, Albert V and Kang, Hyun M and Satpathy, Ansuman T and Natarajan, Pradeep and Kitzman, Jacob O and Whitsel, Eric A and Reiner, Alexander P and Bick, Alexander G and Jaiswal, Siddhartha} } @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} }