Identifying rare variants for genetic risk through a combined pedigree and phenotype approach: application to suicide and asthma

Abstract

Suicidal behavior is a complex disorder, with evidence for genetic risk independent of other genetic risk factors including psychiatric disorders. Since 1996, over 3000 DNA samples from Utah suicide decedents have been collected and banked for research use through the Utah Medical Examiner. In addition, over 12 000 Utah suicides were identified through examination of death certificates back to 1904. By linking this data with the Utah Population Database, we have identified multiple extended pedigrees with increased risk for suicide completion. A number of medical conditions co-occur with suicide, including asthma, and this study was undertaken to identify genetic risk common to asthma and suicide. This study tests the hypothesis that a particular comorbid condition may identify a more homogeneous genetic subgroup, facilitating the identification of specific genetic risk factors in that group. From pedigrees at increased risk for suicide, we identified three pedigrees also at significantly increased familial risk for asthma. Five suicide decedents from each of these pedigrees, plus an additional three decedents not from these pedigrees with diagnosed asthma, and 10 decedents with close relatives with asthma were genotyped. Results were compared with 183 publicly available unaffected control exomes from 1000 Genomes and CEPH (Centre d'etude du polymorphisme humain) samples genotyped on the same platform. A further 432 suicide decedents were also genotyped as non-asthma suicide controls. Genotyping was done using the Infinium HumanExome BeadChip. For analysis, we used the pedigree extension of Variant Annotation, Analysis and Search Tool (pVAAST) to calculate the disease burden of each gene. The Phenotype Driven Variant Ontological Re-ranking tool (Phevor) then re-ranked our pVAAST results in context of the phenotype. Using asthma as a seed phenotype, Phevor traversed biomedical ontologies and identified genes with similar biological properties to those known to result in asthma. Our top associated genes included those related to neurodevelopment or neural signaling (brain-derived neurotrophic factor (BDNF), neutral sphingomyelinase 2 (SMPD2), homeobox b2 (HOXB2), neural cell adhesion molecule (NCAM2), heterogeneous nuclear ribonucleoprotein A0 (HNRNPA0)), inflammation (free fatty acid receptor 2 (FFAR2)) and inflammation with additional evidence of neuronal involvement (oxidized low density lipoprotein receptor 1 (OLR1), toll-like receptor 3 (TLR3)). Of particular interest, BDNF has been previously implicated in both psychiatric disorders and asthma. Our results demonstrate the utility of combining pedigree and co-occurring phenotypes to identify rare variants associated with suicide risk in conjunction with specific co-occurring conditions.

Understanding and predicting suicidality using a combined genomic and clinical risk assessment approach

“…Such a restrictive approach was used as a way of minimizing false positives, even at the risk of having false negatives. For example, there were genes on each of the two lists, from AP and DE analyses, that had clear prior evidence for involvement in suicidality, such as OLR1 10 , 11 (32%) and LEPR 1 , 12 (32%) for AP, and OPRM1 13 , 14 (32%) and CD24 1 , 11 (33%) from DE, but were not included in our subsequent analyses because they did not meet our a priori set 33.3% threshold.…”

Youth Suicide Deaths: Investigation of Clinical Predictors in a Statewide Sample

“…Genetic vulnerability is a well‐studied risk factor for suicide (Brent & Melhem, ; McGuffin, Marusic, & Farmer, ; Pedersen & Fiske, ), with the potential to identify at‐risk cohorts (McGowan et al., ). As part of our own study, the Utah OME has been collecting DNA on suicide completers for over 20 years, and this work has begun to identify specific genetic mutations that may increase suicide risk (Coon et al., ; Darlington et al., ). Given the interesting age, gender, and diagnostic differences discovered in our data, we hope to further refine our genetic studies on youth suicide completers.…”

Antidepressants normalize elevated Toll-like receptor profile in major depressive disorder

“…Maternal immune activation with the TLR3 agonist poly I:C during mid-pregnancy increases anxiety- and depressive-like behaviors. A genome-wide association study identified TLR3 as genetic risk factor for suicide in individuals with asthma and with a familial risk for asthma (Darlington et al 2014 ). A postmortem study identified abnormal TLR3 over-expression in the dorsolateral prefrontal cortex of 22 depressed suicide victims (Pandey et al 2014 ).…”