Gene‐level associations in suicide attempter families show overrepresentation of synaptic genes and genes differentially expressed in brain development

Abstract

Suicidal behavior (SB) has a complex etiology involving different polygenic and environmental components. Here we used an excess of significant markers (ESM) test to study gene‐level associations in previous genome‐wide association studies (GWAS) SNP data from a family‐based sample, having medically severe suicide attempt (SA) as main outcome in the offspring. In SA without major psychiatric disorders (N = 498), a screening of 5,316 genes across the genome suggested association 17 genes (at fdr < 0.05). Genes RETREG1 (a.k.a. FAM134B), GSN, GNAS, and CACNA1D were particularly robust to different methodological variations. Comparison with the more widely used Multi‐marker Analysis of GenoMic Annotation (MAGMA) methods, mainly supported RETREG1, GSN, RNASEH2B, UBE2H, and CACNA1D by using the “mean” model, and ranked 13 of the same genes as ESM among its top‐17. Complementing the ESM screen by using MAGMA to analyze 17,899 genes, we observed excess of genes with p < .05 by using the “top” model, and the “mean” model suggested additional genes with genome‐wide fdr < 0.25. Overrepresentation analysis of 10 selected gene sets using all genes with p < .05, showed significant results for synaptic genes, genes differentially expressed in brain development and for ~12% of the SA polygenic association genes identified previously in this sample. Exploratory analysis linked some of the ESM top‐17 genes to psychotropic drugs and we examined the allelic heterogeneity in the previous SA candidate GRIN2B. This study complemented previous GWAS on SB outcomes, implicating both previous candidate (e.g., GRIN2B and GNAS) and novel genes in SA outcomes, as well as synaptic functions and brain development.

Predictive Potential of Circulating Ube2h mRNA as an E2 Ubiquitin-Conjugating Enzyme for Diagnosis or Treatment of Alzheimer’s Disease

“…This clinical data indicated that Ube2h may be associated with neurodegenerative disorders [16,17]. Moreover, recent genetic studies reported that Ube2h is a meaningful gene in brain development and human brain diseases, such as autistic disorder [16,18]. These results indicated that Ube2h is highly polymorphic, and mutations affect neurodegenerative disorder.…”

Identification of gene ontology and pathways implicated in suicide behavior: Systematic review and enrichment analysis of GWAS studies

“…Initially, the literature search provided 191 articles (PubMed = 97, Scopus = 93) associated to GWAS and suicide. After the methodological inclusion/exclusion criteria, we obtain 21 eligible studies (Table ; Bani‐Fatemi et al, ; Coon et al, ; Erlangsen et al, ; Galfalvy et al, , ; Gross et al, ; Kimbrel et al, ; Laje et al, ; Levey et al, ; Menke et al, ; Mullins et al, ; Perlis et al, ; Perroud et al, ; Pulay & Rethelyi, ; Schosser et al, ; Sokolowski et al, , ; Stein et al, ; Strawbridge et al, ; Willour et al, ; Zai et al, ). Regarding the clinical situation of the individuals included, the behaviors that were mainly studied were SA and SI with frequent psychiatric diagnostics of major depressive disorder or bipolar disorder.…”

“…However, we only considered the GWAS with SB (SA, SI, or SC); therefore, the articles of Laje et al (), Menke et al (), and Perroud et al () were excluded from the enrichment analysis. Concerning this, the genes selected derived from 18 reports (Bani‐Fatemi et al, ; Coon et al, ; Erlangsen et al, ; Galfalvy et al, , ; Gross et al, ; Kimbrel et al, ; Levey et al, ; Mullins et al, ; Perlis et al, ; Pulay & Rethelyi, ; Schosser et al, ; Sokolowski et al, , ; Stein et al, ; Strawbridge et al, ; Willour et al, ; Zai et al, ). These eligible genes were located in chromosomes 1–22, having: (a) nine genes the Chr6, (b) eight genes the Chr1, Chr9, and Chr10, (c) seven genes the Chr2 and Chr8, (d) six genes the Chr3 and Chr14, (e) five genes the Chr4, Chr7, and Chr13, (f) four genes the Chr5, Chr11, (g) Chr12 and Chr15, (h) three genes the Chr17 and Chr18, (i) two genes the Chr16, and (j) one gene the Chr19, Chr20, Chr21, and Chr22, more detail see Table S1.…”

Convergence of recent GWAS data for suicidality with previous blood biomarkers: independent reproducibility using independent methodologies in independent cohorts

“…Since our last publication in 2017, a series of 4 GWAS of suicidality (ideation, attempts) [4,5,6,7], as well as a family based genetic study of suicide completers [8] and a family based genetic study in suicide attempters [9], have been published, in Molecular Psychiatry and other journals.…”

“…Of note, there was no overlap between the top genes implicated by these different recent genetic studies, which raises the issue of apparent lack of reproducibility in the field. We compared the list of top genes implicated by each of the recent genetic studies (genes that were associated with loci/SNPs that were statistically significant and/or were highlighted/discussed by the authors in their paper) [4,5,6,7,8,9], with the list of candidate biomarkers that survived the initial whole-genome discovery step in our previous published studies, before any literature-based prioritization. We sought to see if any of the top genes from the recent genetic studies have functional evidence of tracking suicidal ideation in our blood gene expression biomarker discovery studies.…”