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Study Follows Geographic Impacts on Apparent Heritability of Complex Traits

NEW YORK – New research by a team from the Netherlands has demonstrated the impact that an individual's birthplace and current geography can have on the apparent heritability of human phenotypes profiled by genome-wide association studies, particularly when it comes to educational attainment, income, and other traits with ties to socioeconomic status (SES).

"Effects estimated in GWASs of many phenotypes are affected by gene-environment correlations, and these are not entirely attributable to processes that take place within a family but are also attributable more broadly to regional social, economic, and political processes that correlate with individuals' genotypes," first and corresponding author Abdel Abdellaoui, a psychiatry researcher at the University of Amsterdam, and his colleagues explained in Nature Genetics on Monday.

Based on their findings, the authors argued that "[s]tatistical models, research designs, and conclusions of GWASs need to more carefully reflect the reality of the social and geographic structure of society."

Starting with polygenic scores associated with educational attainment, the researchers profiled gene-environment relationships in nearly 23,700 adult sibling pairs enrolled in the UK Biobank study, demonstrating that these genetic scores contain clues stemming from participants' geography and migration history.

From there, the team extended its analyses to span some 56 complex traits — ranging from cardiovascular- or cognition-related traits to sleep patterns and substance use — in the sibling pairs and in a broader set of almost 254,600 adult UK Biobank participants.

By combining data for more than 1.2 million common SNPs and available geographic clues, the investigators found that trait heritability tended to dip when information on participants' birthplace region and/or current address were considered. That was particularly true for educational attainment and income outcomes, as well as traits such as body mass index (BMI), substance use, and sedentary behavior.

"The most significant reductions in genetic correlations with education and income were observed for traits related to BMI and body fat, suggesting correlations between SES-related genes and obesogenic environments," the authors noted. "This may help (partly) explain why the polygenic score for BMI shows the strongest geographic clustering in Great Britain, after educational attainment and cognition."

The researchers noted that it was possible to dial down such gene-environment effects on GWAS analyses by taking individuals' geography into account, though they cautioned that "[f]ully removing polygenic effects that affect the outcome via the social environment will be more challenging."

"We showed how to significantly reduce these effects in GWAS signals," the authors explained. "It will depend on the goals of the research whether this would be desirable, as these effects result from dynamic social circumstances that are part of a true causal chain in between our DNA and complex mental and physical health outcomes."

Among other potential study limitations, the team noted that the UK Biobank participants considered so far tend to be healthy, highly educated, and come from relatively affluent regions, which may mute some of the socioeconomic effects found across other regions in the UK.

"Geographic clustering of SES is probably stronger in the general population than in UK Biobank," the authors explained, "so effects observed in the current study may be underestimated."