Risk Pathways to Major Depression: Integrating Genetic-Epidemiological, Developmental, and Molecular Genetic Strategies in Danish and Swedish National Registers

Virginia Commonwealth University, Richmond VA

Investigators

Abstract

Project Summary This project seeks to advance our etiological understanding of Major Depression (MD) by clarifying the interrelationships, over developmental time, of genetic and environmental risk factors. These analyses will be conducted using data from Denmark and Sweden - two of the best and most complete population-based registers in the world. Our investigative team brings together individuals with expertise in medical and psychiatric epidemiology, genetic epidemiology, psychiatric nosology, and psychiatric molecular genetics as well as deep experience working in Swedish and Danish registers. We propose seven specific aims. The first two involve harmonizing a wide range of information relevant to risk for MD across the two registers, along with their unique extensions, and then continued development of a methodological innovation key to this proposal: Family Genetic Risk Scores (FGRS). FGRS permits us to assess, based on extensive pedigree information, profiles of multiple genetic scores – capturing risk for MD, related disorders, and other traits that could help dissect etiology - in every individual with family-linkage in the Danish and Swedish populations. Our third aim is to further develop and validate registry-based measures of environmental stressors that reflect i) chronic psychosocial adversities and ii) stressful life events, both of which predispose to MD, although over different time scales. The fourth aim will be to describe differences in the FGRS profiles associated with key clinical characteristics of MD (e.g., age at onset, recurrence, diagnostic stability) and psychiatric comorbidity (e.g., with anxiety or alcohol use disorders) in Denmark and Sweden. The fifth and sixth aims are to integrate what we have learned about MD and its risk factors to develop comprehensive etiologic models for MD that take into account genetic, environmental, and developmental factors, as well as possible differences among subtypes of MD. All analyses using FGRS will be paralleled using polygenic scores (PGS) in the set of individuals genotyped as a part of three Danish biobanks. We hope these analyses can better flesh out etiologic heterogeneity within the broad MD syndrome. The final aim, using molecular genetic resources from Danish biobanks, is to explore the impact for GWAS approaches, guided by our previous aims, to inform on molecular mechanisms of MD. In sum, this project will find substantial power, reproducibility, and robustness in working across comparable nation-wide health, socio-demographic, and familial registers from Denmark (sampling from ~9,500,000 individuals, ~300,000,000 person-years of observation) and Sweden (sampling from ~17,000,00 individuals, ~500,000,000 person-years of observation) and leveraging extensions into primary care registers of Sweden and >500,000 genotyped individuals in Danish biobanks. This project is of relevance to the US as it seeks to gain much needed insights into the etiology of MDD that could guide, in the future, nosology, prevention, and/or intervention. 1