Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression

Abstract

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association (GWA) meta-analysis based in 135,458 cases and 344,901 control, We identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression, and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relations of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine and define the basis of major depression and imply a continuous measure of risk underlies the clinical phenotype.

Predicting loneliness with polygenic scores of social, psychological and psychiatric traits

“…When including only the covariates, only sex and age were significantly associated with loneliness, with women and younger individuals reporting higher levels of loneliness (sex: standardized B = −.124, P = 8.3 × 10 −9 ; age: standardized B = −.071, P = 2.5 × 10 −10 ). Out of the 27 polygenic scores that survived the power analyses, 12 were significantly associated with loneliness when tested separately, with standardized B 's varying between .04 and .08: MDD (2 distinct studies, one based on self-report in a web-based survey, 57 and one on structured clinical interviews, clinician-administered checklists, hospital/medical records or self-report 58 ), neuroticism (2 distinct studies, one based on a web-based implementation of the Big Five Inventory (BFI), 59 and one on a combination of the NEO Personality Inventory, Eysenck Personality Questionnaire and the International Personality and Item Pool Inventory 61 ), schizophrenia, subjective well-being, the genes shared between schizophrenia and bipolar disorder, depressive symptoms, tiredness, bipolar disorder, conscientiousness and self-rated health ( P < .002; see Figure 1). Polygenic scores for extraversion, anorexia, openness and autism reached nominal significance ( P < .05).…”

“…One MDD index was based on a recent large GWAS conducted by 23andMe, 57 where clinical diagnoses of depression were identified through self-report in web-based surveys. The second score was based on a GWAS from the Psychiatric Genomics Consortium, 58 where cases were identified through structured diagnostic instruments from direct interviews by trained interviewers, clinician-administered Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) checklists, hospital/medical records or self-reported clinical diagnoses. It is not clear whether the difference between the unique genetic risks captured by the 2 scores are due to a difference in the phenotype or sample ascertainment or due to chance fluctuations in effect-size estimates of individual SNPs between studies.…”

<b><i>VRK2</i></b>, a Candidate Gene for Psychiatric and Neurological Disorders

“…Indeed, GWAS of psychiatric disorders have led to the identification of multiple novel risk variants with known or unknown function relevant to the biology of illnesses [23-25], and substantial progress has been obtained toward understanding the genetic architecture and molecular pathogeneses (e.g., dendritic spine pathology) of these psychiatric disorders [26, 27]. Among the risk candidates discovered through SCZ and MDD GWAS studies [13-20], VRK2 (vaccinia-related kinase 2) is one of the few genes showing consistent genome-wide significant associations with both disorders. In addition, this gene has been implicated in a variety of neurological disorders, further supporting its potential roles in the central nervous system.…”

Analyzing the genes and pathways related to major depressive disorder via a systems biology approach

“…The epsilon-4 type allele of APOE is found to be associated with depression in patients with Alzheimer's disease (Delano-Wood et al, 2008). In line with this view, more and more genes have been found to be potentially associated with MDD (Wray et al, 2018). Similar to other complex mental disorders, genetic studies have suggested that for MDD, the individual differences may be caused by multiple genes and their variants.…”