Dataset Information

Gene × physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry.

ABSTRACT: Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction ?=?0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n?=?39,810, Pinteraction ?=?0.014 vs. n?=?71,611, Pinteraction ?=?0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction ?=?0.003) and the SEC16B rs10913469 (Pinteraction ?=?0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.

SUBMITTER: Ahmad S

PROVIDER: S-EPMC3723486 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Gene × physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry.

Ahmad Shafqat S Rukh Gull G Varga Tibor V TV Ali Ashfaq A Kurbasic Azra A Shungin Dmitry D Ericson Ulrika U Koivula Robert W RW Chu Audrey Y AY Rose Lynda M LM Ganna Andrea A Qi Qibin Q Stančáková Alena A Sandholt Camilla H CH Elks Cathy E CE Curhan Gary G Jensen Majken K MK Tamimi Rulla M RM Allin Kristine H KH Jørgensen Torben T Brage Soren S Langenberg Claudia C Aadahl Mette M Grarup Niels N Linneberg Allan A Paré Guillaume G Magnusson Patrik K E PK Pedersen Nancy L NL Boehnke Michael M Hamsten Anders A Mohlke Karen L KL Pasquale Louis T LT Pedersen Oluf O Scott Robert A RA Ridker Paul M PM Ingelsson Erik E Laakso Markku M Hansen Torben T Qi Lu L Wareham Nicholas J NJ Chasman Daniel I DI Hallmans Göran G Hu Frank B FB Renström Frida F Orho-Melander Marju M Franks Paul W PW

PLoS genetics 20130725 7

Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated ...[more]

PMID: 23935507

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Project description:IntroductionHeritability estimates of nicotine dependence (ND) range from 40% to 70%, but discovery GWAS of ND are underpowered and have limited predictive utility. In this work, we leverage genetically correlated traits and diseases to increase the accuracy of polygenic risk prediction.MethodsWe employed a multi-trait model using summary statistic-based best linear unbiased predictors (SBLUP) of genetic correlates of DSM-IV diagnosis of ND in 6394 individuals of European Ancestry (prevalence = 45.3%, %female = 46.8%, µ age = 40.08 [s.d. = 10.43]) and 3061 individuals from a nationally-representative sample with Fagerström Test for Nicotine Dependence symptom count (FTND; 51.32% female, mean age = 28.9 [s.d. = 1.70]). Polygenic predictors were derived from GWASs known to be phenotypically and genetically correlated with ND (i.e., Cigarettes per Day [CPD], the Alcohol Use Disorders Identification Test [AUDIT-Consumption and AUDIT-Problems], Neuroticism, Depression, Schizophrenia, Educational Attainment, Body Mass Index [BMI], and Self-Perceived Risk-Taking); including Height as a negative control. Analyses controlled for age, gender, study site, and the first 10 ancestral principal components.ResultsThe multi-trait model accounted for 3.6% of the total trait variance in DSM-IV ND. Educational Attainment (β = -0.125; 95% CI: [-0.149,-0.101]), CPD (0.071 [0.047,0.095]), and Self-Perceived Risk-Taking (0.051 [0.026,0.075]) were the most robust predictors. PGS effects on FTND were limited.ConclusionsRisk for ND is not only polygenic, but also pleiotropic. Polygenic effects on ND that are accessible by these traits are limited in size and act additively to explain risk.ImplicationsThese findings enhance our understanding of inherited genetic factors for nicotine dependence. The data show that genome-wide association study (GWAS) findings across pre- and comorbid conditions of smoking are differentially associated with nicotine dependence and that when combined explain significantly more trait variance. These findings underscore the utility of multivariate approaches to understand the validity of polygenic scores for nicotine dependence, especially as the power of GWAS of broadly-defined smoking behaviors increases. Realizing the potential of GWAS to inform complex smoking behaviors will require similar theory-driven models that reflect the myriad of mechanisms that drive individual differences.

Dataset Information

Gene × physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry.

Publications

Gene × physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry.

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