Jerominski, L. | Search bioRxiv

bioRxiv2017

Identification of genome-wide significant shared genomic segments in large extended Utah families at high risk for completed suicide

Suicide is the 10th leading cause of death in the US. While environment has undeniable impact, evidence suggests genetic factors play a significant role in completed suicide. We linked a resource of >4,500 DNA samples from completed suicides obtained from the Utah Medical Examiner to genealogical records and medical records data available on over 8 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 to 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. While 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 in ~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.

genetics↗

bioRxiv2017

High-risk Autism Spectrum Disorder Utah pedigrees: a novel Shared Genomic Segments analysis.

Progress in gene discovery for Autism Spectrum Disorder (ASD) has been rapid over the past decade, with major successes in validation of risk of predominantly rare, penetrant, de novo and inherited mutations in over 100 genes (de Rubies et al., 2015; Sanders et al., 2015). However, the majority of individuals with ASD diagnoses do not carry a rare, penetrant genetic risk factor. In fact, recent estimates suggest that most of the genetic liability of ASD is due to as yet undiscovered common, less penetrant inherited variation (Gaugler et al., 2014) which is much more difficult to detect. The study of extended, high-risk families adds significant information in our search for these common inherited risk factors. Here, we present results of a new, powerful pedigree analysis method (Shared Genomic Segments--SGS) on three large families from the Utah Autism Research Program. The method improves upon previous methods by allowing for within-family heterogeneity, and identifying exact region boundaries and subsets of cases who share for targeted follow-up analyses. Our SGS analyses identified one genome-wide significant shared segment on chromosome 17 (q21.32, p=1.47x10-8). Additional regions with suggestive evidence were identified on chromosomes 3, 4, 6, 8, 11, 13, 14, 15, and 18. Several of these segments showed evidence of sharing across families. Genes of interest in these regions include ATP8A1, DOCK3, CACNA2D2, ITGB3, AMBRA1, FOLH1, DGKZ, MTHFS, ARNT2, BTN2A2, BTN3A1, BTN3A3, BTN2A1, and BTN1A1. We are exploring multiple other lines of evidence to follow up these implicated regions and genes.

genetics↗