Polygenic Risk Scores Reveal Patterns of Assortative Mating And Anticipation In A Large Pedigree Affected With Mood Disorders

Abstract

Background Psychiatric disorders are leading causes of disability globally. Worldwide prevalence rates for mood disorders range from around 1% for Bipolar disorder (BP) to 5.7% for Major Depressive Disorder (MDD). Having a first-degree relative with a psychiatric disorder is a significant risk factor for developing the same or a related psychiatric disorder, and heritability estimates range from moderate for MDD (~40%) to high for BP (80-90%). This indicates a significant genetic component in their etiology, which is likely comprises a combination of rare and common genetic variation. The aim of this study is to examine the role that common genetic variation confers on disease risk in a severely affected pedigree that would have traditionally been viewed through the prism of monogenic inheritance only. Methods To achieve this we exploit both a large pedigree (n~300) with high prevalence of mood disorders (30% of family members is affected with major depressive disorder (MDD) or bipolar disorder (BP)) and the recently popular polygenic risk score (PRS) approach. Illumina Psych chip data is available for 243 family members of which 78 individuals are affected with mood disorders (including 36 BP and 38 MDD patients) and 57 unrelated healthy Brazilian controls. Using psychiatric PRS derived from recent large GWAS mega analysis efforts in psychiatric disorders like schizophrenia (SCZ), BP and MDD, we examine patterns of assortative mating and anticipation in the family. Results First, we examine common variant effect on risk via an association between PRS and case/control status in the pedigree. Next we investigate an increase in PRS value across the generations, seemingly driven by the transmission of elevated PRS to offspring from 46 affected married-in individuals. This suggests that PRS contributions from married-in individuals, caused by assortative mating on phenotype, may increase risk for psychiatric disorders beyond that conferred by rare variation transmitted from within the family. Discussion Leveraging results from the SCZ2 mega analysis into PRS allowed us to investigate the relationship between common genetic variation and patterns of assortative mating and anticipation in a complex multigenerational pedigree affected with mood disorders. A joint analysis of both rare and common variation may be the most powerful way to understand the familial genetics of mood and psychiatric disorders.