Suicide is the 10th leading cause of death in the United States. Although environment has undeniable impact, evidence suggests that genetic factors play a significant role in completed suicide. We linked a resource of~4500 DNA samples from completed suicides obtained from the Utah Medical Examiner to genealogical records and medical records data available on over eight million individuals. This linking has resulted in the identification of high-risk extended families (7-9 generations) with significant familial risk of completed suicide. Familial aggregation across distant relatives minimizes effects of shared environment, provides more genetically homogeneous risk groups, and magnifies genetic risks through familial repetition. We analyzed Illumina PsychArray genotypes from suicide cases in 43 high-risk families, identifying 30 distinct shared genomic segments with genome-wide evidence (p = 2.02E-07-1.30E-18) of segregation with completed suicide. The 207 genes implicated by the shared regions provide a focused set of genes for further study; 18 have been previously associated with suicide risk. Although PsychArray variants do not represent exhaustive variation within the 207 genes, we investigated these for specific segregation within the high-risk families, and for association of variants with predicted functional impact iñ 1300 additional Utah suicides unrelated to the discovery families. None of the limited PsychArray variants explained the high-risk family segregation; sequencing of these regions will be needed to discover segregating risk variants, which may be rarer or regulatory. However, additional association tests yielded four significant PsychArray variants (SP110, rs181058279; AGBL2, rs76215382; SUCLA2, rs121908538; APH1B, rs745918508), raising the likelihood that these genes confer risk of completed suicide.
Identification of genetic factors leading to increased risk of suicide death is critical to combat rising suicide rates, however, only a fraction of the genetic variation influencing risk has been accounted for. To address this limitation, we conducted the first comprehensive analysis of rare genetic variation in suicide death leveraging the largest suicide death biobank, the Utah Suicide Genetic Risk Study (USGRS). We conducted a single-variant association analysis of rare (minor allele frequency <1%) putatively functional single-nucleotide polymorphisms (SNPs) present on the Illumina PsychArray genotyping array in 2,672 USGRS suicide deaths of non-Finnish European (NFE) ancestry and 51,583 NFE controls from the Genome Aggregation Database. Secondary analyses used an independent control sample of 21,324 NFE
Variation in traits can be owing to genetic factors or the environment – nature versus nurture – or more likely, a combination of both. It may be of interest, especially when a trait is detrimental, to localise the regions of the genome that contain the genes involved and beyond that, to map specific risk variants. Understanding the possible roles that genes may play in trait variation and, furthermore, estimating or modelling the genetic component are important first steps to inform subsequent genetic studies. There are many different study designs and genetic analysis techniques, each with their respective strengths and weaknesses for the identification of risk variants. Knowledge of disease susceptibility genes may help in the quest for new treatments and cures. Key Concepts Types of trait variation. The possible roles of genes in trait variation. The components of phenotypic variation. Study designs for the estimation of genetic effects and heritability. Genetic heterogeneity. Types of genetic study designs. Various analysis techniques used in genetic studies.
Suicide is the 10th leading cause of death in the US. While environment has undeniable impact, evidence suggests that genetic factors play a major role in completed suicide. We have >4,500 DNA samples from completed suicides through a collaboration with the Utah Medical Examiner. We have linked the records from these cases to the Utah Population Database which includes multi-generation genealogies, demographic data, and medical information on over 8 million individuals. This linking has resulted in extended families (7-9 generations) with significant familial risk of completed suicide. Familial aggregation across distant relatives minimizes effects of shared environment, provides more genetically homogeneous risk groups, and magnifies genetic risks through familial repetition. We analyzed DNA from 215 suicide cases in 43 of our largest high-risk families and identified 16 regions with genome-wide significance in 10 families. Of the 163 genes in these regions, 25% were associated with psychiatric risk. We also found 13 regions with genome-wide suggestive evidence where the region overlaps in >1 family (p-values from 4.63E-09 to <1E-16). Of the 101 genes in these overlapping regions, seven have been previously associated with suicide risk (RGS18, BRINP3, RHEB, CDK5, CTNNA3, STAT1, and HTR2A); only one gene with specific suicide risk would have been expected by chance. Our most significant region on chromosome 5q23.3 was shared by 21 cases across three families. This region contains several genes associated with both psychiatric conditions and inflammation: HINT1, RAPGEF6, ACSL6, IL3, SLC22A4, CSF2, and IRF1. Our study provides 249 genes in the significant regions in our study represent important new candidate genes for suicide. The genome-wide significant family-specific regions may reveal more rare risk variants, while risk variants in regions that overlap across families may be more common.. CC-BY-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/195644 doi: bioRxiv preprint first posted online Sep. 28, 2017; 3 Author SummarySuicide is the 10th leading cause of death in the US. While environment has undeniable impact, evidence suggests that genetic factors play a major role in completed suicide. We have used DNA from suicide cases related to each other in very large extended high-risk families (7-9 generations) to discover regions of the genome likely to contain genetic changes leading to increased suicide risk. Studying these distantly related cases minimizes effects of shared environment and allows us to detect genetic risks more easily through their familial repetition. The genomic regions discovered in this study of our 43 largest high-risk families contained seven genes with corroborating evidence of association with suicide from previous studies, in addition to many genes with known psychiatric assoc...
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