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Non-Random Mating May Exaggerate Findings of Pleiotropy in Population Genetic Studies

NEW YORK – Genetic overlap between traits may be overestimated by failing to consider non-random mating patterns, according to an international team that analyzed dozens of genetic trait associations taking "cross-trait assortative mating" — dubbed xAM — into account.

"Together, our results demonstrate that previous reports have likely overestimated the true genetic similarity between many phenotypes," first and corresponding author Richard Border, a postdoctoral researcher at the University of California, Los Angeles, and his colleagues wrote in Science on Thursday.

Using genetic data for nearly 40,700 "spousal pairs" enrolled in the UK Biobank project, along with almost 373,3000 couples from a Danish population study, the researchers analyzed xAM impacts on the variants implicated in 20 phenotypic traits and half a dozen psychiatric conditions.

Together with computer simulations looking at genotype and phenotype patterns over time, the team's analyses suggested that shared phenotypes in individuals who chose each other as mates may artificially boost apparent genetic ties between certain traits, explaining a significant proportion of potential genetic correlation between these traits.

Moreover, Border noted in a statement, this effect stretched into traits that do appear somewhat linked to one another, artificially enhancing the extent of their relationship.

"[E]ven when there is a real signal there, we’re still suggesting that we’re overestimating the extent of that sharing," he explained.

The overlap between cross-trait genetic contributors and the presence of shared traits or conditions within couples was particularly pronounced for psychiatric conditions such as schizophrenia, bipolar disorder, major depressive disorder, anxiety disorder, alcohol use disorder, or attention deficit hyperactivity disorder, the team explained.

Although genetic correlations persisted for certain conditions after adjusting for xAM, the researchers suggested that the broader findings hint that past research may have overestimated pleiotropy between other pairs of psychiatric conditions that are not as biologically related to one another.

"The observation of genetic correlations between disparate human traits has been interpreted as evidence of widespread pleiotropy," the authors explained, calling xAM "an alternative explanation" and "a form of population structure not captured by conventional principal-component- or mixed-model-based correction."

"Given the increasing evidence that existing methods fail to completely address structural factors, even in ostensibly ancestrally homogeneous groups, a broader characterization of population structure and methods for addressing such structure will likely be necessary to generate results that are maximally clinically relevant and can be applied equitably," members of the team concluded.

In a related perspectives article, Andrew Grotzinger and Matthew Keller, researchers affiliated with the University of Colorado Boulder's Institute of Behavioral Genetics and its psychology and neuroscience department, suggested that the new results "make it clear that more realistic models for why mates correlate within and between multiple traits need to be developed and tested."

"[M]ore complete models of the mechanisms through which observed levels of xAM manifest will be important for obtaining a better understanding of downstream effects on [genetic correlation estimates]," Grotzinger and Keller noted.