Integrated Bayesian analysis of rare exonic variants to identify risk genes for schizophrenia and neurodevelopmental disorders.

Genome Med
Authors
Keywords
Abstract

BACKGROUND: Integrating rare variation from trio family and case-control studies has successfully implicated specific genes contributing to risk of neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASD), intellectual disability (ID), developmental disorders (DDs), and epilepsy (EPI). For schizophrenia (SCZ), however, while sets of genes have been implicated through the study of rare variation, only two risk genes have been identified.

METHODS: We used hierarchical Bayesian modeling of rare-variant genetic architecture to estimate mean effect sizes and risk-gene proportions, analyzing the largest available collection of whole exome sequence data for SCZ (1,077 trios, 6,699 cases, and 13,028 controls), and data for four NDDs (ASD, ID, DD, and EPI; total 10,792 trios, and 4,058 cases and controls).

RESULTS: For SCZ, we estimate there are 1,551 risk genes. There are more risk genes and they have weaker effects than for NDDs. We provide power analyses to predict the number of risk-gene discoveries as more data become available. We confirm and augment prior risk gene and gene set enrichment results for SCZ and NDDs. In particular, we detected 98 new DD risk genes at FDR 0.55), but low between SCZ and the NDDs (ρ

CONCLUSIONS: We have extended a pipeline used in ASD studies and applied it to infer rare genetic parameters for SCZ and four NDDs ( https://github.com/hoangtn/extTADA ). We find many new DD risk genes, supported by gene set enrichment and PPI network connectivity analyses. We find greater similarity among NDDs than between NDDs and SCZ. NDD gene subnetworks are implicated in postnatally expressed presynaptic and postsynaptic genes, and for transcriptional and post-transcriptional gene regulation in prenatal neural progenitor and stem cells.

Year of Publication
2017
Journal
Genome Med
Volume
9
Issue
1
Pages
114
Date Published
2017 Dec 20
ISSN
1756-994X
DOI
10.1186/s13073-017-0497-y
PubMed ID
29262854
PubMed Central ID
PMC5738153
Links
Grant list
R01 MH095034 / MH / NIMH NIH HHS / United States
R01MH105554 / National Institute of Mental Health
R01 MH077139 / National Institute for Health Research
R01MH110555 / National Institute of Mental Health
R01 MH077139 / National Institutes of Health (US)
R01 MH110555 / MH / NIMH NIH HHS / United States
U01 MH109528 / MH / NIMH NIH HHS / United States
R01 MH077139 / National Institutes of Health
R01 MH109903 / MH / NIMH NIH HHS / United States