Biological constraints on GWAS SNPs at suggestive significance thresholds reveal additional BMI loci

eLife

Alessandra Chesi¹  Rudolph L Leibel²  Sumei Lu³  Chiara Lasconi³  Yadav Wagley³  James A Pippin³  Matthew C Pahl³  Diana L Cousminer³  Matthew E Johnson⁴  Kenyaita M Hodge⁴  Claudia A Doege⁴  Michelle E Leonard⁴  Struan FA Grant⁴  Reza K Hammond⁴  Chun Su⁴  Andrew D Wells⁵  Kurt D Hankenson⁶ 

[1] Columbia Stem Cell Initiative, Vagelos College of Physicians and Surgeons, Columbia University, New York, United States;Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, United States;Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, United States;Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia, Philadelphia, United States;Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, United States;Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, United States;

关键词: bioinformatics;    GWAS;    functional genomics;    Capture C;    body mass index;    waist-hip ratio;   

DOI  :  10.7554/eLife.62206

来源: DOAJ

【 摘 要 】

To uncover novel significant association signals (p<5×10−8), genome-wide association studies (GWAS) requires increasingly larger sample sizes to overcome statistical correction for multiple testing. As an alternative, we aimed to identify associations among suggestive signals (5 × 10−8≤p<5×10−4) in increasingly powered GWAS efforts using chromatin accessibility and direct contact with gene promoters as biological constraints. We conducted retrospective analyses of three GIANT BMI GWAS efforts using ATAC-seq and promoter-focused Capture C data from human adipocytes and embryonic stem cell (ESC)-derived hypothalamic-like neurons. This approach, with its extremely low false-positive rate, identified 15 loci at p<5×10−5 in the 2010 GWAS, of which 13 achieved genome-wide significance by 2018, including at NAV1, MTIF3, and ADCY3. Eighty percent of constrained 2015 loci achieved genome-wide significance in 2018. We observed similar results in waist-to-hip ratio analyses. In conclusion, biological constraints on sub-significant GWAS signals can reveal potentially true-positive loci for further investigation in existing data sets without increasing sample size.

【 授权许可】

Unknown