BBFGEN · Genetic analysis of rare and common variation in a large Brazilian bipolar family

Genetic analysis of rare and common variation in a large Brazilian bipolar family

For this project we set out to improve understanding of the genetic underpinnings of mood disorders. For this we utilized a unique dataset comprising a large multigenerational family, the Brazilian Bipolar Family (BBF). This family not only exhibits high incidence of depression and bipolar disorders (approximately one third of family is affected) but also features diminishing age of onset over generations and assortative mating, whereby many of the marriages in the family are between individuals both affected with a psychiatric disorder. Mood disorders are severe and leading contributors to the global burden of disease. Bipolar disorder (BP) features periods of elevated mood and periods of depression, while major depressive disorder (MDD) is characterized by pervasive and persistent low mood, low self-esteem and loss of interest or pleasure in normally enjoyable activities. Heritability estimates are ~40% for MDD and up to 80% for BP, indicating a large role for genetic vulnerability for developing mood disorders. The genetic architecture is thought to consist of both common and rare variants contributing risk. My objective was to unravel the role of both rare and common genetic variation within a family context with the ultimate goal of examining the interaction between both types of genetic risk variation. The BBF provides a unique opportunity for achieving this goal. Within this framework we carried out three main studies, where we first find rare genetic variation associated to mood disorders in the family through traditional linkage analysis. Subsequently, we define common genetic risk through polygenic risk score profiles; in essence summing the small risk over thousands of common alleles per individual. Our results suggest that affected individuals marrying into the family (assortative mating) introduce a higher load of common risk variants for psychiatric disorders on top of the rare risk variants already present. This also appears to increase the contribution of common genetic risk factors over generations, in parallel with the diminishing age of onset. Finally, this reversal of risk type over generations is visible when combining these two analyses in an integrative analysis.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз