Sex differences in the genetic architecture of depression

Abstract

The prevalence and clinical characteristics of depressive disorders differ between women and men; however, the genetic contribution to sex differences in depressive disorders has not been elucidated. To evaluate sex-specific differences in the genetic architecture of depression, whole exome sequencing of samples from 1000 patients (70.7% female) with depressive disorder was conducted. Control data from healthy individuals with no psychiatric disorder (n = 72, 26.4% female) and East-Asian subpopulation 1000 Genome Project data (n = 207, 50.7% female) were included. The genetic variation between men and women was directly compared using both qualitative and quantitative research designs. Qualitative analysis identified five genetic markers potentially associated with increased risk of depressive disorder in females, including three variants (rs201432982 within PDE4A, and rs62640397 and rs79442975 within FDX1L) mapping to chromosome 19p13.2 and two novel variants (rs820182 and rs820148) within MYO15B at the chromosome 17p25.1 locus. Depressed patients homozygous for these variants showed more severe depressive symptoms and higher suicidality than those who were not homozygotes (i.e., heterozygotes and homozygotes for the non-associated allele). Quantitative analysis demonstrated that the genetic burden of protein-truncating and deleterious variants was higher in males than females, even after permutation testing. Our study provides novel genetic evidence that the higher prevalence of depressive disorders in women may be attributable to inherited variants.

Genetic Markers for Later Remission in Response to Early Improvement of Antidepressants

“…All statistical analyses were conducted using R 3.5.3 ( ). As genetic vulnerabilities in depression risk and antidepressant response have been shown to be different between sexes [ 20 , 21 ], all analyses were conducted on the total population and separately on men and women.…”

“…This study was performed to uncover genetic markers for predicting non-remission in patients exhibiting poor early improvement using WES data from a depression cohort ( n = 1000) undergoing 12 weeks of antidepressant treatment with a naturalistic design. To decrease the limitation of sample heterogeneity, separate analyses were performed according to sex due to evidence indicating that there are differences between the sexes in terms of the effects of genetic vulnerabilities on depression risk [ 20 ] and antidepressant responses [ 21 ]. To consider the complex effects of multiple variants and their interactions on antidepressant response within genes as functional units, the gene-wise variant burden (GVB) scoring approach reflecting the cumulative contributions of several variants in specific genes [ 22 ] was used in the present analyses instead of polygenic risk scores, which do not yield reliable predictions of antidepressant response [ 23 ].…”

Prediction of Major Depressive Disorder Following Beta-Blocker Therapy in Patients with Cardiovascular Diseases

“…A previous study found that the lifetime prevalence of major depressive episodes was higher in females than in males and the onset was earlier in females [ 37 ]. This difference may arise from behavioral characteristics and fundamental genetic reasons [ 38 , 39 ]. In addition, perimenopausal disorder may contribute to the female sex being predictive of MDD, as shown in our model and a previous study [ 40 ].…”

Placenta DNA methylation atZNF300is associated with fetal sex and placental morphology

“…Genetic variation may help this understanding. Sex-specific differences in the effects of genetic risk factors on health outcomes have been reported [32] including for mortality rates after injury [33], susceptiblity to immune diseases [34], response to vaccination [35], chronic obstructive pulmonary disease risk [36], basal cell carcinoma [37], cardiometabolic disorders [38,39], and depression [40,41]. Genetic variation in placental tissue has also been shown to impact birth outcomes including large for gestational age [42], birthweight [43,44], and preterm birth [45], but studies to investigate differences in genetic risks by sex or to identify genetic variant associations with placenta size and morphology are lacking.…”