Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences

Abstract

Humans vary substantially in their willingness to take risks. In a combined sample of over one million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated (|truer^g| ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near general-risk-tolerance-associated SNPs are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.

Evaluating the effects of alcohol and tobacco use on cardiovascular disease using multivariable Mendelian randomization

“…We included all SNPs associated at genome-wide significance (P < 5 x 10 -8 ) (we use the standard heuristic significance threshold for these dimensional MR to make the work manageable) with the phenotype "drinks per week" (DPW), constructed, for UK Biobank participants who indicated they drank "at least once or twice per week", by aggregating the weekly intake of distilled spirts (pub measures), beer and cider (pints), red wine, white wine, and champagne (glasses), and other alcoholic drinks e.g. alcopops (DPW: mean = 8.92 drinks, SD = 9.30 drinks) 32 . (For UK Biobank participants who indicated they drank "one to three times a month", the phenotype was constructed by aggregating the monthly intake over all drink types and dividing by four.)…”

“…For tobacco use, we extracted SNPs from the companion GWAS meta-analysis of 518,633 individuals of predominantly European ancestry (444,598 from the UK Biobank prospective cohort study and 74 035 from the Tobacco, Alcohol and Genetics (TAG) Consortium) 32 . We included all SNPs associated at genome-wide significance with the phenotype "ever smoker status" (a binary phenotype coded "1" if the individual reported he or she was a previous or current smoker, "0" if he or she had never smoked or only smoked once or twice).…”

“…Given the complexity of the relationship between alcohol and CVDs, average alcohol consumption may not be sufficient to evaluate the risk conferred for CVDs 28 . There is observational evidence for a link with approximately 85% of smokers drinking alcohol 29 , and drinkers are 75% more likely than abstainers to smoke 30 , as well as a strong genetic correlation 31,32 . Thus, failure to account for smoking in previous single variable MR analyses (SVMR) of alcohol and CVDs may have produced biased and inconsistent estimates.…”

“…Using a two-sample MR design ( Fig. 1), we created instruments for alcohol and tobacco use using summary statistics from publicly available, large-scale genome-wide association studies (GWAS) 32 (Table 1 and Supplementary Table 1) to evaluate the potential causal effects thereof on cardiovascular disease risk factors and disease events.…”

Insights into the aetiology of snoring from observational and genetic investigations in the UK Biobank (n=408,317)

“…We performed a follow-up sensitivity GWAS for snoring including BMI as a covariate to explore the effects of BMI on associated variants. The results revealed 97 genome-wide significant SNPs across 34 genomic risk loci ( Figure 2) with overall SNP heritability on the liability 16 , RNA5SP471 16,17 and SND1 and NSUN3, previously associated with alcohol consumption; 14,[16][17][18] FTO and SND1, associated with coffee consumption; 19 LMO4 associated with insomnia; 20 and RNA5SP471 with narcolepsy. 20,21 Also, ROBO2, previously associated with chronotype; 22,23 and multiple genes (DLEU7, MSRB3, FTO, ANAPC4, SMG6, SND1, SIM1, KCNQ5, CEP120, MACF1, SNAP91 and BCL2) previously associated with musculoskeletal traits such as height and heel bone mineral density (Supplementary File 1 and Supplementary File 2).…”