Applications

Polygenic interactions with environmental factors in the etiologies of depression, anxiety disorder, obesity and substance use.

Depression, anxiety disorders, obesity and substance use disorders (SUD) are common diseases, and a major cause of long-term disability and mortality worldwide[1,2]. Family and twin studies have shown that depression, anxiety, obesity and SUD are heritable, with estimated heritabilities of around 37% for major depression[3], 32% for generalized anxiety disorder[4], 46% for body mass index (BMI)[5], 57% for alcohol dependence[6] and 67% for nicotine dependence[6], respectively. There is a longstanding recognition that both genes and environment contribute to these diseases, where twin studies show that environmental effects account for 63% of the phenotypic variance of major depression[3]. It is well established that environmental factors, including childhood trauma, social deprivation, stress exposure, diet, and so forth are important risk factors for these diseases, but we still know little about whether these environmental effects are moderated by genetic variation and, if so, which genetic variants are relevant[7].  

Depression, anxiety disorder, obesity and SUD are polygenic diseases, and the study of gene by environment interactions (G x E) can be done by using polygenic risk scores (PRSs), which capture the cumulative effect of many common variants in a single measure[8]. For example, G x E studies have tested whether the effect of childhood trauma (CT) on MDD is moderated by depression PRSs. Inconsistent effects have been found, with a Dutch study showing a positive interaction (CT and high a PRS leading to elevated risks compared to the additive effects of each), while this was not present in a UK study[9, 10]. Most G×E studies to date have focused on a limited set of (or even single) candidate genes rather than PRSs, and very often these studies took place in small samples that were statistically underpowered[7]. Through the recent progress in finding new loci in GWA studies, and through robust PRSs given recent large GWA studies, much further work has become possible to dissect the genetic and environmental contributions to depression, anxiety

year of approval

2020

institute

  • • University Medical Center Groningen

primary applicant

  • Snieder, H.