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WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE.

ABSTRACT: Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10^-9). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

SUBMITTER: Zhang X

PROVIDER: S-EPMC10473809 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE.

Zhang Xinruo X Brody Jennifer A JA Graff Mariaelisa M Highland Heather M HM Chami Nathalie N Xu Hanfei H Wang Zhe Z Ferrier Kendra K Chittoor Geetha G Josyula Navya S NS Li Xihao X Li Zilin Z Allison Matthew A MA Becker Diane M DM Bielak Lawrence F LF Bis Joshua C JC Boorgula Meher Preethi MP Bowden Donald W DW Broome Jai G JG Buth Erin J EJ Carlson Christopher S CS Chang Kyong-Mi KM Chavan Sameer S Chiu Yen-Feng YF Chuang Lee-Ming LM Conomos Matthew P MP DeMeo Dawn L DL Du Margaret M Duggirala Ravindranath R Eng Celeste C Fohner Alison E AE Freedman Barry I BI Garrett Melanie E ME Guo Xiuqing X Haiman Chris C Heavner Benjamin D BD Hidalgo Bertha B Hixson James E JE Ho Yuk-Lam YL Hobbs Brian D BD Hu Donglei D Hui Qin Q Hwu Chii-Min CM Jackson Rebecca D RD Jain Deepti D Kalyani Rita R RR Kardia Sharon L R SLR Kelly Tanika N TN Lange Ethan M EM LeNoir Michael M Li Changwei C Marchand Loic Le LL McDonald Merry-Lynn N MN McHugh Caitlin P CP Morrison Alanna C AC Naseri Take T O'Connell Jeffrey J O'Donnell Christopher J CJ Palmer Nicholette D ND Pankow James S JS Perry James A JA Peters Ulrike U Preuss Michael H MH Rao D C DC Regan Elizabeth A EA Reupena Sefuiva M SM Roden Dan M DM Rodriguez-Santana Jose J Sitlani Colleen M CM Smith Jennifer A JA Tiwari Hemant K HK Vasan Ramachandran S RS Wang Zeyuan Z Weeks Daniel E DE Wessel Jennifer J Wiggins Kerri L KL Wilkens Lynne R LR Wilson Peter W F PWF Yanek Lisa R LR Yoneda Zachary T ZT Zhao Wei W Zöllner Sebastian S Arnett Donna K DK Ashley-Koch Allison E AE Barnes Kathleen C KC Blangero John J Boerwinkle Eric E Burchard Esteban G EG Carson April P AP Chasman Daniel I DI Chen Yii-Der Ida YI Curran Joanne E JE Fornage Myriam M Gordeuk Victor R VR He Jiang J Heckbert Susan R SR Hou Lifang L Irvin Marguerite R MR Kooperberg Charles C Minster Ryan L RL Mitchell Braxton D BD Nouraie Mehdi M Psaty Bruce M BM Raffield Laura M LM Reiner Alexander P AP Rich Stephen S SS Rotter Jerome I JI Shoemaker M Benjamin MB Smith Nicholas L NL Taylor Kent D KD Telen Marilyn J MJ Weiss Scott T ST Zhang Yingze Y Heard-Costa Nancy N Sun Yan V YV Lin Xihong X Adrienne Cupples L L Lange Leslie A LA Liu Ching-Ti CT Loos Ruth J F RJF North Kari E KE Justice Anne E AE

medRxiv : the preprint server for health sciences 20230822

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (<i>P</i> < 5 × 10<sup>-9</sup>). Notab ...[more]

PMID: 37662265

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Project description:Race, specifically African ancestry, and obesity are important risk factors for uterine fibroids, and likely interact to provide the right conditions for fibroid growth. However, existing studies largely focus on the main-effects rather than their interaction. Here, we firstly provide evidence for interaction between categories of body mass index (BMI) and reported-race in relation to uterine fibroids. We then investigate whether the association between inferred local European ancestry and fibroid risk is modified by BMI in African American (AA) women in the Vanderbilt University Medical Center bio-repository (BioVU) (539 cases and 794 controls) and the Coronary Artery Risk Development in Young Adults study (CARDIA, 264 cases and 173 controls). We used multiple logistic regression to evaluate interactions between local European ancestry and BMI in relation to fibroid risk, then performed fixed effects meta-analysis. Statistical significance threshold for local-ancestry and BMI interactions was empirically estimated with 10,000 permutations (p-value = 1.18x10-4). Admixture mapping detected an association between European ancestry and fibroid risk which was modified by BMI (continuous-interaction p-value = 3.75x10-5) around ADTRP (chromosome 6p24); the strongest association was found in the obese category (ancestry odds ratio (AOR) = 0.51, p-value = 2.23x10-5). Evaluation of interaction between genotyped/imputed variants and BMI in this targeted region suggested race-specific interaction, present in AAs only; strongest evidence was found for insertion/deletion variant (6:11946435), again in the obese category (OR = 1.66, p-value = 1.72x10-6). We found nominal evidence for interaction between local ancestry and BMI at a previously reported region in chromosome 2q31-32, which includes COL5A2, and TFPI, an immediate downstream target of ADTRP. Interactions between BMI and SNPs (single nucleotide polymorphisms) found in this region in AA women were also detected in an independent European American population of 1,195 cases and 1,164 controls. Findings from our study provide an example of how modifiable and non-modifiable factors may interact to influence fibroid risk and suggest a biological role for BMI in fibroid etiology.

Project description:BackgroundGenome-wide association studies of obesity have typically assumed fixed genetic effects across ethnicities, rarely attempting to thoroughly compare and contrast findings across various ethnic groups. Therefore, our study aimed to identify novel genetic associations with body mass index (BMI), a common measure of obesity, and explore their cross-ethnic generalizability in a multiethnic population. To that end, we conducted ethnic-specific genome-wide association analyses among 1235 Hispanic, 706 Asian, 1549 African American, and 2395 European American subjects from the Multi-ethnic Study of Atherosclerosis (MESA). We compared findings across ethnicities and investigated single-nucleotide polymorphisms (SNPs) with suggestive BMI-association p-values among 3379 Hispanic and 6871 African American subjects from the Women's Health Initiative (WHI).ResultsWe identified a genome-wide significant association in MESA Hispanics-rs12253976 in KLF6 (beta = 5.792 kg/m(2) per-allele, 95 % confidence interval (CI): 3.885, 7.698; p = 3.43 × 10(-9))-and suggestive SNPs with p < 5 × 10(-6) in MESA Hispanics, European Americans and African Americans that display ethnic-specific effects on BMI. Of these suggestive SNPs, Hispanic SNP rs12255372 and African American SNP rs6435678 had the most evidence of replication in WHI. rs12255372 (in TCF7L2) was associated with lower BMI in both MESA (beta = -1.111 kg/m(2), 95 % CI: -1.578, -0.645; p = 3.33 × 10(-6)) and WHI Hispanics (beta = -0.304 kg/m(2), 95 % CI: -0.613, 0.006; p = 0.054). This TCF7L2 intronic region contains several SNPs (rs7901695, rs4506565, rs4132670, and rs12243326) with low p-values (p < 10(-3)) in MESA and betas of similar magnitude and direction in MESA and WHI, but only rs12243326 is in strong linkage disequilibrium with rs12255372 in our Hispanic populations, suggesting independent signals in this region. rs6435678 (in ERBB4) was associated with greater BMI in both MESA (beta = 1.104 kg/m(2), 95 % CI: 0.643, 1.564; p = 2.85 × 10(-6)) and WHI African Americans (beta = 0.219 kg/m(2), 95 % CI: -0.021, 0.460; p = 0.074).ConclusionsTwo BMI-association signals are present in the TCF7L2 intronic region of Hispanics, one of which is tagged by rs12255372. ERBB4 rs6435678 is a novel BMI-association signal in African Americans. Overall, our data suggest that ethnic-specific associations are involved in the genetic determination of BMI. Ethnic-specificity has potential implications for the development of gene-based therapies for obesity.

Dataset Information

WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE.

Publications

WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE.

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