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

Planning subsequent treatment strategies based on early responses rather than waiting for delayed antidepressant action can be helpful. We identified genetic markers for later non-remission in patients exhibiting poor early improvement using whole-exome sequencing data of depressive patients treated in a naturalistic manner. Among 1000 patients, early improvement at 2 weeks (reduction in Hamilton Depression Rating Scale [HAM-D] score ≥ 20%) and remission at 12 weeks (HAM-D score ≤ 7) were evaluated. Gene- and variant-level analyses were conducted to compare patients who did not exhibit early improvement and did not eventually achieve remission (n = 126) with those who exhibited early improvement and achieved remission (n = 385). Genes predicting final non-remission in patients who exhibited poor early improvement (COMT, PRNP, BRPF3, SLC25A40, and CGREF1 in males; PPFIBPI, LZTS3, MEPCE, MAP1A, and PFAS in females; ST3GAL5 in the total population) were determined. Among the significant genes, variants in the PRNP (rs1800014), COMT (rs6267), BRPF3 (rs200565609), and SLC25A40 genes (rs3213633) were identified. However, interpretations should be made cautiously, as complex pharmacotherapy involves various genes and pathways. Early detection of poor early improvement and final non-remission based on genetic risk would be helpful for decision-making in a clinical setting.

Genetic markers for depressive disorders with earlier age at onset.

Age at onset has been considered a potential indicator of underlying genetic risk in depression research. However, the variants associated with earlier age at onset of depressive disorder have not been elucidated. To evaluate the genetic architecture of depression onset, whole-exome sequencing of samples from 1000 patients with depressive disorder was performed. Cox proportional hazard models with false discovery rate-adjusted P-values were used to estimate the hazard ratios; carriers and non-carriers of individual coding variants were compared in terms of age at onset of depression with adjustment for sociodemographic and clinical characteristics. The clinical relevance of the candidate variants was also examined. Whole-exome sequencing revealed four variants in the CCL14, FYB, GPRASP1, and CTNND2 genes associated with an increased risk of depressive disorder with earlier age at onset. Although no individual variant was associated with any clinical characteristic except AAO, together they were associated with younger AAO, younger age at visit for treatment, and recurrent and atypical depression. Our data suggest novel candidate genes for depressive disorder with earlier age at onset. These genes could serve as markers allowing early identification of patients at risk of depression, and thus earlier intervention.

Sex differences in the genetic architecture of depression.

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.

Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects.

BACKGROUND: Ritodrine is a commonly used tocolytic to prevent preterm labour. However, it can cause unexpected serious adverse reactions, such as pulmonary oedema, pulmonary congestion, and tachycardia. It is unknown whether such adverse reactions are associated with pharmacogenomic variants in patients. METHODS: Whole-exome sequencing of 13 subjects with serious ritodrine-induced cardiac and pulmonary side-effects was performed to identify causal genes and variants. The deleterious impact of nonsynonymous substitutions for all genes was computed and compared between cases (n = 13) and controls (n = 30). The significant genes were annotated with Gene Ontology (GO), and the associated disease terms were categorised into four functional classes for functional enrichment tests. To assess the impact of distributed rare variants in cases with side effects, we carried out rare variant association tests with a minor allele frequency ≤ 1% using the burden test, the sequence Kernel association test (SKAT), and optimised SKAT. RESULTS: We identified 28 genes that showed significantly lower gene-wise deleteriousness scores in cases than in controls. Three of the identified genes-CYP1A1, CYP8B1, and SERPINA7-are pharmacokinetic genes. The significantly identified genes were categorized into four functional classes: ion binding, ATP binding, Ca2+-related, and ciliopathies-related. These four classes were significantly enriched with ciliary genes according to SYSCILIA Gold Standard genes (P < 0.01), thus representing ciliary genes. Furthermore, SKAT showed a marginal trend toward significance after Bonferroni correction with Joubert Syndrome ciliopathy genes (P = 0.05). With respect to the pharmacokinetic genes, rs1048943 (CYP1A1) and rs1804495 (SERPINA7) showed a significantly higher frequency in cases than controls, as determined by Fisher's exact test (P < 0.05 and P < 0.01, respectively). CONCLUSIONS: Ritodrine-induced cardiac and pulmonary side effects may be associated with deleterious genetic variants in ciliary and pharmacokinetic genes.