A genomewide linkage study on suicidality in major depressive disorder confirms evidence for linkage to 2p12

Abstract

Suicidal behavior is commonly associated with depression. Twin studies indicate that both suicidality and major depressive disorder (MDD) are heritable. However, epidemiological evidence suggests that the inheritance of suicidality is likely to be independent of the underlying psychiatric disorder, implying a distinct genetic contribution to suicidality. We conducted a genomewide linkage search aiming to detect genomic loci that may harbor susceptibility genes contributing to risk for suicidality in recurrent MDD. Affected sibling pair (ASP) variance components analysis was performed using the Depression Network cohort of 971 ASPs. The quantitative trait measuring suicidality as a broad phenotype, encompassing ideation and suicide attempts, was established from Schedules for Clinical Assessment in Neuropsychiatry interview items. We examined 1,060 genotyped microsatellite markers with an average spacing of 3.3 cM. Empirical thresholds for linkage evidence were set by whole-genome simulations (LOD = 2.71 for genomewide significance, 1.71 for suggestive linkage). No genomewide significant findings were found. Marker D3S1234 on 3p14 achieved suggestive linkage and yielded a maximum LOD of 1.853 (P = 0.0017), loci 9p24.3 and 18q22-q23 achieved LOD scores >1.5. We found some support for linkage to 2p12 (LOD = 1.2, P = 0.0087) which was previously implicated in linkage studies of suicidality. Our follow-up meta-analysis of five studies showed strong linkage to this region (P = 2 × 10(-6) ). In conclusion, this study analyzed suicidality as a continuous trait in MDD. We found modest evidence for linkage on 3p14. Our meta-analysis supports previous evidence of linkage to suicidality on 2p12. Some candidate genes in these regions may plausibly be implicated in suicidality. © 2010 Wiley-Liss, Inc.

The impact of serotonin receptor 1A and 2A gene polymorphisms and interactions on suicide attempt and suicide risk in depressed patients with insufficient response to treatment – a European multicentre study

“…Twin, adoption and family studies have indicated that both suicidal behaviour and MDD are genetically modulated (Brent and Mann, 2005;Butler et al, 2010). It is estimated that ∼ 30 million individuals per year are affected by MDD within the European Union, with a lifetime risk for suicide with up to 15% (Davies et al, 2001;Wittchen et al, 2011).…”

Genome-wide association studies of suicidal behaviors: A review

“…Only GWAS which assayed SNPs were included. Linkage studies were excluded and have been reviewed elsewhere (Butler et al, 2010). Power for single SNP-associations (Table 1) …”

“…However, a combined meta-analysis analysis of both the discovery and replication samples yielded a genome-wide significant association for SNP rs300774 (which also showed the lowest p-value in the discovery sample). LD-analysis of SNP rs300774 showed it was located in a large LD-block containing three genes (SH3YL1, ACP1 and FAM150B), as well as being near a consistently demonstrated linkage peak (at 2p11-12) for suicide attempts (Butler et al, 2010). Strength of the study is that they then assessed gene-expression data and found RNA expression changes in the prefrontal cortex of bipolar suicides for ACP1 (but not SH3YL1) and thus proposed the SNP association to be involved in ACP1 functions.…”

RE: Butler AW et al. 2010. A genomewide linkage study on suicidality in major depressive disorder confirms evidence for linkage to 2p12. Am J Med genet part B 153B(8):1465–1473.

“…In a recent report, Butler et al [2010] presented the results of a genome-wide linkage analysis of a quantitative suicidality trait in recurrent Major Depressive Disorder (R-MDD). Although the investigators failed to find genome-wide significant linkage at any region, they reported evidence in support of linkage near D2S1777 on chromosome 2p12, as well as meta-analysis of previous linkage analyses in the region that yielded a combined P-value of 2 Â 10…”

“…The studies chosen by Butler et al for consideration in their meta-analysis included families ascertained through different diagnostic phenotypes, and these studies employed different affected mood phenotypes, diverse suicide phenotypes, and different statistical methods for linkage analysis. Furthermore, in an attempt to replicate the results of their MSP meta-analysis, we can approximate their findings (P $ 10 À6 ) only by including the results from the Butler et al [2010], Willour et al [2007], and Hesselbrock et al [2004] studies, and excluding the results reported in the studies of Cheng et al [2006] and Zubenko et al [2004]. Importantly, these first three studies are exclusively those that Butler et al contend reported previous positive findings, an approach that would lead to a biased estimate.…”