An Integrative Approach to the Etiology of Internalizing Disorders in the Lifelines Cohort
Internalizing Disorders (IDs) account for a substantial proportion of global disease burden, are highly
comorbid and share common etiologic pathways. However, progress in understanding the causal
mechanisms underlying IDs has been slow. The overall aim of this project is to clarify the etiology,
course and comorbidities of five major internalizing disorders (Major Depression [MD], Dysthymia [DYS],
Generalized Anxiety disorder [GAD] and Panic Disorder [PD], Social Phobia [SPH] in Lifelines, a
prospective population-based cohort in North-Eastern Netherlands following 167,729 adult subjects
with assessments of psychiatric and general medical health every five years. Lifelines includes high
quality data on the phenotypes, environments, genotypes, and microbiome of multiple generations of
family members and detailed assessments of the IDs as well as the three major functional disorders
(FDs) (Chronic Fatigue Syndrome [CFS], Fibromyalgia [FM] and Irritable Bowel Syndrome [IBS]) which are
highly comorbid with IDs. The richness of this data allows for an in-depth analysis of disease
mechanisms. We will build multivariate models that include the phenotypic, environmental, familial, and
molecular genetic levels to understand which of the mechanisms are shared amongst versus specific to
the 5 IDs and 3 associated FDs. To meet these goals, we propose three specific aims. In our first aim, we
will investigate, utilizing a range of causal inference and multivariate methods, the etiologic relations
between IDs and between IDs and FDs, leveraging the rich longitudinal and family structure of Lifelines.
Our second aim will be to use advanced genetic epidemiologic and molecular genetic methods applied
to both family structure and genome wide SNP data to clarify the shared and unique risk factors for IDs
and between ID and FDs. We will re-look at causal inter-relationships among our disorders using
Mendelian Randomization. Building on aims 1 and 2, our third aim will investigate the joint action and
interaction of genetic and environmental risk factors on the development(s) of IDs and FDs. This will
include examining the effects of genetic nurture. We will again be using complimentary methods to
examine gene x environment interactions utilizing methods from both genetic epidemiology and
molecular genetics. To conduct this cross-disciplinary research, we have assembled, over the last 5
years, a broad collaborative team from the Virginia Institute for Psychiatric and Behavioral Genetics at
VCU and the departments of Psychiatry and Genetics at the University Medical Center Groningen,
Netherlands.