Genetic risk factors in two Utah pedigrees at high risk for suicide

Abstract

We have used unique population-based data resources to identify 22 high-risk extended pedigrees that show clustering of suicide over twice that expected from demographically adjusted incidence rates. In this initial study of genetic risk factors, we focused on two high-risk pedigrees. In the first of these (pedigree 12), 10/19 (53%) of the related suicides were female, and the average age at death was 30.95. In the second (pedigree 5), 7/51 (14%) of the suicides were female and the average age at death was 36.90. Six decedents in pedigree 12 and nine in pedigree 5 were genotyped with the Illumina HumanExome BeadChip. Genotypes were analyzed using the Variant Annotation, Analysis, and Search program package that computes likelihoods of risk variants using the functional impact of the DNA variation, aggregative scoring of multiple variants across each gene and pedigree structure. We prioritized variants that were: (1) shared across pedigree members, (2) rare in other Utah suicides not related to these pedigrees, (3) ⩽ 5% in genotyping data from 398 other Utah population controls and (4) ⩽5% frequency in publicly available sequence data from 1358 controls and/or in dbSNP. Results included several membrane protein genes (ANO5, and TMEM141 for pedigree 12 and FAM38A and HRCT1 for pedigree 5). Other genes with known neuronal involvement and/or previous associations with psychiatric conditions were also identified, including NFKB1, CASP9, PLXNB1 and PDE11A in pedigree 12, and THOC1, and AUTS2 in pedigree 5. Although the study is limited to variants included on the HumanExome BeadChip, these findings warrant further exploration, and demonstrate the utility of this high-risk pedigree resource to identify potential genes or gene pathways for future development of targeted interventions.

PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain

“…Consistent with this idea, the RNAseq experiment shows that PDE11A KO mice exhibit a significant reduction relative to PDE11A WT and HT mice in insulin-like growth factor binding protein 3 (IGFBP3), elevated expression of which is associated with chronic loneliness in humans (Cole et al, 2007). Although some questions remain, data presented here strongly argue that PDE11A is a key regulator of social interactions, which is consistent with the fact that PDE11A has been genetically and/or functionally associated with clinical phenotypes related to changes in social function, including major depressive disorder (Wong et al, 2006; Couzin, 2008; Cabanero et al, 2009; Luo et al, 2009; Kelsoe, 2010; Coon et al, 2013), suicide risk (an inactivating mutation, (Coon et al, 2013)), and lithium responsivity (Couzin, 2008; Kelsoe, 2010; Mertens et al, 2015; Pathak et al, in press). …”

“…1A) (Kelly et al, 2010, 2014; Kelly, 2014, 2015; Hegde et al, 2016; Pathak et al, in press) and little to no expression in peripheral organs (c.f., (Kelly, 2015)). PDE11A has been genetically and/or functionally associated with clinical phenotypes related to changes in social function, including major depressive disorder (Wong et al, 2006; Cabanero et al, 2009; Luo et al, 2009), suicide risk (an inactivating mutation, (Coon et al, 2013)), and lithium responsivity (Couzin, 2008; Kelsoe, 2010; Mertens et al, 2015; Pathak et al, in press). Previously, we showed that reducing PDE11A expression was sufficient to reduce social approach behavior towards a novel mouse in adult male mice, but not female mice (Kelly et al, 2010).…”

A unified test of linkage analysis and rare-variant association for analysis of pedigree sequence data

“…Although pVAAST is primarily designed for sequence data, it is also applicable to exome chip genotyping data. pVAAST was recently used to identify candidate genes associated with an increased risk of suicide from exome chip data in extended high-risk pedigrees 28 .…”

Epigenetic Dysregulation in the Prefrontal Cortex of Suicide Completers

“…table 3) which have been associated with the development of suicide [for reviews, see Turecki et al, 2012;Coon et al, 2013;Mandelli and Seretti, 2013;Sadkowski et al, 2013]. Fifteen (10%) of these 145 genes have been replicated in independent studies ( table 2 ); BDNF , HTR1A , HTR1B , SLC6A4 (5-HTTLPR) , SSAT (SAT1) , TPH1 , and TPH2 even showed association in multiple studies.…”