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Risky Behavior Tied to Hundreds of Loci Through Large GWAS Analysis

NEW YORK (GenomeWeb) – Researchers have identified hundreds of loci associated with risky behaviors among people.

People's willingness to take risks varies, though twin studies have suggested that risk tolerance is moderately heritable. An international team of researchers has conducted a large genome-wide association study of general risk tolerance and six supplemental studies of related phenotypes, such as adventurousness or ever having been a smoker using data from the UK Biobank and the consumer genetic testing firm 23andMe.

As the researchers reported in Nature Genetics today, they found a number of shared genetic influences across people's general tolerance to risk and particular risky behaviors. These genetic influences highlighted the involvement of glutamatergic and GABAergic neurotransmission pathways, but not other pathways that had previously been implicated in risk tolerance.

"Our results provide insights into biological mechanisms that influence general risk tolerance," the University of Toronto's Jonathan Beauchamp and his colleagues wrote in their paper. The team included researchers from 23andMe.

For their GWAS of overall tolerance to risk, the researchers drew upon more than 431,000 individuals from the UK Biobank, into which they then folded nearly 509,000 23andMe research participants for an additional meta-analysis. These individuals had answered questions about whether they considered themselves risk takers or felt comfortable taking risks.

Through this, the researchers identified 124 SNPs residing at 99 loci that reached genome-wide significance.

To replicate these findings, they performed a meta-analysis using summary statistics from 10 smaller cohorts, which covered 123 of the 124 SNPs found in the discovery phase. Of those, 23 were significant.

The research team also conducted supplementary GWAS of adventurousness, four risky behaviors — tendency to speed while driving, number of drinks per week, smoking, and number of sexual partners — and the first principal component of those risky behaviors. These analyses uncovered 740 lead associations.

They noted a high level of overlap across their results. Of the 99 general risk-tolerance loci, 46 also contained a lead SNP from at least one of the other GWAS. Of the 124 general risk-tolerance lead SNPs, 72 were in weak linkage disequilibrium with a lead SNP from at least one other GWAS.

When they then estimated genetic correlations with general risk tolerance, the researchers found the correlations with the six supplementary phenotypes to all be positive and were largest for adventurousness and number of sexual partners. When they expanded this analysis to include more than two dozen other phenotypes, the researchers further noted genetic correlations between general risk tolerance and personality traits like extraversion and neuroticism, and neuropsychiatric conditions like attention deficit hyperactivity disorder, bipolar disorder, and schizophrenia.

The researchers traced these loci back to what genetic pathways they may influence. They in particular examined whether the SNPs they uncovered fell within genes associated with biological pathways thought to be involved in risk-taking like the cortisol, dopamine, serotonin, estrogen, and testosterone pathways. However, using the MAGMA competitive gene-set analysis tool, they found no evidence these pathways were enriched among their findings.

Instead, they used the Gene Network database and the DEPICT software tool to uncover that the glutamate and GABA neurotransmitters — excitatory and inhibitory transmitters within the brain — may be involved. These pathways, the researchers noted, had not before been linked to risk tolerance.

These analyses also implicated the prefrontal cortex and basal ganglia — brain regions involved in learning, motivation, and decision-making — in risk tolerance.