TY - JOUR
T1 - GEM
T2 - scalable and flexible gene-environment interaction analysis in millions of samples
AU - Westerman, Kenneth E.
AU - Pham, Duy T.
AU - Hong, Liang
AU - Chen, Ye
AU - Sevilla-González, Magdalena
AU - Sung, Yun Ju
AU - Sun, Yan V.
AU - Morrison, Alanna C.
AU - Chen, Han
AU - Manning, Alisa K.
N1 - Publisher Copyright:
© The Author(s) 2021.
PY - 2021/10/15
Y1 - 2021/10/15
N2 - Motivation: Gene-environment interaction (GEI) studies are a general framework that can be used to identify genetic variants that modify the effects of environmental, physiological, lifestyle or treatment effects on complex traits. Moreover, accounting for GEIs can enhance our understanding of the genetic architecture of complex diseases and traits. However, commonly used statistical software programs for GEI studies are either not applicable to testing certain types of GEI hypotheses or have not been optimized for use in large samples. Results: Here, we develop a new software program, GEM (Gene-Environment interaction analysis in Millions of samples), which supports the inclusion of multiple GEI terms, adjustment for GEI covariates and robust inference, while allowing multi-threading to reduce computation time. GEM can conduct GEI tests as well as joint tests of genetic main and interaction effects for both continuous and binary phenotypes. Through simulations, we demonstrate that GEM scales to millions of samples while addressing limitations of existing software programs. We additionally conduct a gene-sex interaction analysis on waist-hip ratio in 352 768 unrelated individuals from the UK Biobank, identifying 24 novel loci in the joint test that have not previously been reported in combined or sex-specific analyses. Our results demonstrate that GEM can facilitate the next generation of large-scale GEI studies and help advance our understanding of the genetic architecture of complex diseases and traits.
AB - Motivation: Gene-environment interaction (GEI) studies are a general framework that can be used to identify genetic variants that modify the effects of environmental, physiological, lifestyle or treatment effects on complex traits. Moreover, accounting for GEIs can enhance our understanding of the genetic architecture of complex diseases and traits. However, commonly used statistical software programs for GEI studies are either not applicable to testing certain types of GEI hypotheses or have not been optimized for use in large samples. Results: Here, we develop a new software program, GEM (Gene-Environment interaction analysis in Millions of samples), which supports the inclusion of multiple GEI terms, adjustment for GEI covariates and robust inference, while allowing multi-threading to reduce computation time. GEM can conduct GEI tests as well as joint tests of genetic main and interaction effects for both continuous and binary phenotypes. Through simulations, we demonstrate that GEM scales to millions of samples while addressing limitations of existing software programs. We additionally conduct a gene-sex interaction analysis on waist-hip ratio in 352 768 unrelated individuals from the UK Biobank, identifying 24 novel loci in the joint test that have not previously been reported in combined or sex-specific analyses. Our results demonstrate that GEM can facilitate the next generation of large-scale GEI studies and help advance our understanding of the genetic architecture of complex diseases and traits.
UR - http://www.scopus.com/inward/record.url?scp=85123428812&partnerID=8YFLogxK
U2 - 10.1093/bioinformatics/btab223
DO - 10.1093/bioinformatics/btab223
M3 - Article
AN - SCOPUS:85123428812
SN - 1367-4803
VL - 37
SP - 3514
EP - 3520
JO - Bioinformatics
JF - Bioinformatics
IS - 20
ER -