Large-scale interaction effects reveal missing heritability in schizophrenia, bipolar disorder and posttraumatic stress disorder

Abstract

Genetic susceptibility factors behind psychiatric disorders typically contribute small effects individually. A possible explanation for the missing heritability is that the effects of common variants are not only polygenic but also non-additive, appearing only when interactions within large groups are taken into account. Here, we tested this hypothesis for schizophrenia (SZ) and bipolar disorder (BP) disease risks, and identified genetic factors shared with posttraumatic stress disorder (PTSD). When considered independently, few single-nucleotide polymorphisms (SNPs) reached genome-wide significance. In contrast, when SNPs were selected in groups (containing up to thousands each) and the collective effects of all interactions were estimated, the association strength for SZ/BP rose dramatically with a combined sample size of 7187 cases and 8309 controls. We identified a large number of genes and pathways whose association was significant only when interaction effects were included. The gene with highest association was CSMD1, which encodes a negative regulator of complement activation. Pathways for glycosaminoglycan (GAG) synthesis exhibited strong association in multiple contexts. Taken together, highly associated pathways suggested a pathogenesis mechanism where maternal immune activation causes disruption of neurogenesis (compounded by impaired cell cycle, DNA repair and neuronal migration) and deficits in cortical interneurons, leading to symptoms triggered by synaptic pruning. Increased risks arise from GAG deficiencies causing complement activation and excessive microglial action. Analysis of PTSD data sets suggested an etiology common to SZ/BP: interneuron deficiency can also lead to impaired control of fear responses triggered by trauma. We additionally found PTSD risk factors affecting synaptic plasticity and fatty acid signaling, consistent with the fear extinction model. Our results suggest that much of the missing heritability of psychiatric disorders resides in non-additive interaction effects.

Collective interaction effects associated with mammalian behavioral traits reveal genetic factors connecting fear and hemostasis

“…For these simulations, we used the dominant model to reduce the computational cost of enumerating all possible genotypes. For all other computations using animal trait data, we used the genotypic model, which includes the dominant model as a special case and generally enhances the power to infer associations relative to the dominant model [ 12 ].…”

“…We implemented and used a meta-analysis scheme for collective inference involving multiple sub-samples [ 12 , 29 ] (two in this work). Each sample was first divided into training and test sets, and the training sets were used to infer single-SNP and interaction parameters separately for each sub-sample.…”

“…The mouse data set typically contained groups of neighboring SNPs with near perfect LD; before association testing, we used PLINK [ 32 ] (window size 50 bp shifted by 5 SNPs, LD threshold 0.9) to prune the SNP set of a given pathway, and then stratified the set into two covariate-dependent subgroups and performed collective inference meta-analysis. We chose this pruning procedure on the basis of our previous work showing that pathway-based association tests are insensitive to local LD, typically from 1.0 to ~ 0.5 [ 10 , 12 ]. Pruning with a threshold of 0.9 substantially reduced the number of SNPs for each pathway in the mouse data set, allowing for consideration of much larger pathways than without pruning.…”

“…Here, we report the development of an analytical method to infer collective genetic associations of a group of SNPs with quantitative traits. In this method, which is analogous to a similar approach for binary case-control phenotypes [ 10 – 12 ], pre-selected groups of variants (e.g., genes or pathways) are tested for their association with phenotypes while taking into account the distributions of both genotypes and phenotypes within the cohort.…”

Whole Exome Sequencing: Novel Genetic Polymorphisms in Saudi Arabian Attention Deficit Hyperactivity Disorder (ADHD) Children

“…It binds to motifs that regulate HIV gene expression [54]. A study has shown that the HIVEP1 gene was one of the highest ranked-genes to be related to mental disorders such as schizophrenia [37], bipolar disease (BP) and post-traumatic stress disorder (PTSD) [55]. The findings from our study have revealed an SNP (rs2228209) in the HIVEP1 gene that could potentially be linked to ADHD.A body of evidence has shown that SNPs in the integrin alpha 1 ITGA1 gene may cause ADHD.…”