Dataset Information

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

ABSTRACT: Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

SUBMITTER: Graff M

PROVIDER: S-EPMC8059339 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Graff Mariaelisa M Justice Anne E AE Young Kristin L KL Marouli Eirini E Zhang Xinruo X Fine Rebecca S RS Lim Elise E Buchanan Victoria V Rand Kristin K Feitosa Mary F MF Wojczynski Mary K MK Yanek Lisa R LR Shao Yaming Y Rohde Rebecca R Adeyemo Adebowale A AA Aldrich Melinda C MC Allison Matthew A MA Ambrosone Christine B CB Ambs Stefan S Amos Christopher C Arnett Donna K DK Atwood Larry L Bandera Elisa V EV Bartz Traci T Becker Diane M DM Berndt Sonja I SI Bernstein Leslie L Bielak Lawrence F LF Blot William J WJ Bottinger Erwin P EP Bowden Donald W DW Bradfield Jonathan P JP Brody Jennifer A JA Broeckel Ulrich U Burke Gregory G Cade Brian E BE Cai Qiuyin Q Caporaso Neil N Carlson Chris C Carpten John J Casey Graham G Chanock Stephen J SJ Chen Guanjie G Chen Minhui M Chen Yii-Der I YI Chen Wei-Min WM Chesi Alessandra A Chiang Charleston W K CWK Chu Lisa L Coetzee Gerry A GA Conti David V DV Cooper Richard S RS Cushman Mary M Demerath Ellen E Deming Sandra L SL Dimitrov Latchezar L Ding Jingzhong J Diver W Ryan WR Duan Qing Q Evans Michele K MK Falusi Adeyinka G AG Faul Jessica D JD Fornage Myriam M Fox Caroline C Freedman Barry I BI Garcia Melissa M Gillanders Elizabeth M EM Goodman Phyllis P Gottesman Omri O Grant Struan F A SFA Guo Xiuqing X Hakonarson Hakon H Haritunians Talin T Harris Tamara B TB Harris Curtis C CC Henderson Brian E BE Hennis Anselm A Hernandez Dena G DG Hirschhorn Joel N JN McNeill Lorna Haughton LH Howard Timothy D TD Howard Barbara B Hsing Ann W AW Hsu Yu-Han H YH Hu Jennifer J JJ Huff Chad D CD Huo Dezheng D Ingles Sue A SA Irvin Marguerite R MR John Esther M EM Johnson Karen C KC Jordan Joanne M JM Kabagambe Edmond K EK Kang Sun J SJ Kardia Sharon L SL Keating Brendan J BJ Kittles Rick A RA Klein Eric A EA Kolb Suzanne S Kolonel Laurence N LN Kooperberg Charles C Kuller Lewis L Kutlar Abdullah A Lange Leslie L Langefeld Carl D CD Le Marchand Loic L Leonard Hampton H Lettre Guillaume G Levin Albert M AM Li Yun Y Li Jin J Liu Yongmei Y Liu Youfang Y Liu Simin S Lohman Kurt K Lotay Vaneet V Lu Yingchang Y Maixner William W Manson JoAnn E JE McKnight Barbara B Meng Yan Y Monda Keri L KL Monroe Kris K Moore Jason H JH Mosley Thomas H TH Mudgal Poorva P Murphy Adam B AB Nadukuru Rajiv R Nalls Mike A MA Nathanson Katherine L KL Nayak Uma U N'Diaye Amidou A Nemesure Barbara B Neslund-Dudas Christine C Neuhouser Marian L ML Nyante Sarah S Ochs-Balcom Heather H Ogundiran Temidayo O TO Ogunniyi Adesola A Ojengbede Oladosu O Okut Hayrettin H Olopade Olufunmilayo I OI Olshan Andrew A Padhukasahasram Badri B Palmer Julie J Palmer Cameron D CD Palmer Nicholette D ND Papanicolaou George G Patel Sanjay R SR Pettaway Curtis A CA Peyser Patricia A PA Press Michael F MF Rao D C DC Rasmussen-Torvik Laura J LJ Redline Susan S Reiner Alex P AP Rhie Suhn K SK Rodriguez-Gil Jorge L JL Rotimi Charles N CN Rotter Jerome I JI Ruiz-Narvaez Edward A EA Rybicki Benjamin A BA Salako Babatunde B Sale Michele M MM Sanderson Maureen M Schadt Eric E Schreiner Pamela J PJ Schurmann Claudia C Schwartz Ann G AG Shriner Daniel A DA Signorello Lisa B LB Singleton Andrew B AB Siscovick David S DS Smith Jennifer A JA Smith Shad S Speliotes Elizabeth E Spitz Margaret M Stanford Janet L JL Stevens Victoria L VL Stram Alex A Strom Sara S SS Sucheston Lara L Sun Yan V YV Tajuddin Salman M SM Taylor Herman H Taylor Kira K Tayo Bamidele O BO Thun Michael J MJ Tucker Margaret A MA Vaidya Dhananjay D Van Den Berg David J DJ Vedantam Sailaja S Vitolins Mara M Wang Zhaoming Z Ware Erin B EB Wassertheil-Smoller Sylvia S Weir David R DR Wiencke John K JK Williams Scott M SM Williams L Keoki LK Wilson James G JG Witte John S JS Wrensch Margaret M Wu Xifeng X Yao Jie J Zakai Neil N Zanetti Krista K Zemel Babette S BS Zhao Wei W Zhao Jing Hua JH Zheng Wei W Zhi Degui D Zhou Jie J Zhu Xiaofeng X Ziegler Regina G RG Zmuda Joe J Zonderman Alan B AB Psaty Bruce M BM Borecki Ingrid B IB Cupples L Adrienne LA Liu Ching-Ti CT Haiman Christopher A CA Loos Ruth R Ng Maggie C Y MCY North Kari E KE

American journal of human genetics 20210312 4

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combine ...[more]

PMID: 33713608

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Project description:Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

Project description:ObjectiveSerum uric acid is the end-product of purine metabolism and at high levels is a risk factor for several human diseases including gout and cardiovascular disease. Heritability estimates range from 0.32 to 0.63. Genome-wide association studies (GWAS) provide an unbiased approach to identify loci influencing serum uric acid. Here, we performed the first GWAS for serum uric acid in continental Africans, with replication in African Americans.MethodsAfricans (n = 4126) and African Americans (n = 5007) were genotyped on high-density GWAS arrays. Efficient mixed model association, a variance component approach, was used to perform association testing for a total of ~ 18 million autosomal genotyped and imputed variants. CAVIARBF was used to fine map significant regions.ResultsWe identified two genome-wide significant loci: 4p16.1 (SLC2A9) and 11q13.1 (SLC22A12). At SLC2A9, the most strongly associated SNP was rs7683856 (P = 1.60 × 10-44). Conditional analysis revealed a second signal indexed by rs6838021 (P = 5.75 × 10-17). Gene expression and regulatory motif data prioritized a single-candidate causal variant for each signal. At SLC22A12, the most strongly associated SNP was rs147647315 (P = 6.65 × 10-25). Conditional analysis and functional annotation prioritized the missense variant rs147647315 (R (Arg) > H (His)) as the sole causal variant. Functional annotation of these three signals implicated processes in skeletal muscle, subcutaneous adipose tissue and the kidneys, respectively.ConclusionsThis first GWAS of serum uric acid in continental Africans identified three associations at two loci, SLC2A9 and SLC22A12. The combination of weak linkage disequilibrium in Africans and functional annotation led to the identification of candidate causal SNPs for all three signals. Each candidate causal variant implicated a different cell type. Collectively, the three associations accounted for 4.3% of the variance of serum uric acid.

Dataset Information

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Publications

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

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