Abstract
Despite the strongly held view that schizophrenia (SZ) shows substantial genetic heterogeneity, pathway heterogeneity, as seen in cancer where different pathways are affected in similar tumors, has not been explored. We explore this possibility in a case-only study of the neuregulin signaling pathway (NSP), which has been prominently implicated in SZ and for which there is detailed knowledge on the ligand- and receptor-processing steps through β- and γ-secretase cleavage. We hypothesize that more than one damaging variants in the NSP genes might be necessary to cause disease, leading to an apparent clustering of such variants in only the few patients with affected NSP. We analyze linkage and next-generation sequencing results for the genes encoding components of the pathway, including NRG1, NRG3, ERBB4, β-secretase and the γ-secretase complex. We find multiple independent examples of supporting evidence for this hypothesis: (i) increased linkage scores over NSP genes, (ii) multiple positive interlocus correlations of linkage scores across families suggesting each family is linked to either many or none of the genes, (iii) aggregation of predicted damaging variants in a subset of individuals and (iv) significant phenotypic differences of the subset of patients carrying such variants. Collectively, our data strongly support the hypothesis that the NSP is affected by multiple damaging variants in a subset of phenotypically distinct patients. On the basis of this, we propose a general model of pathway heterogeneity in SZ, which, in part, may explain its phenotypic variability and genetic complexity.
Highlights
Schizophrenia (SZ) is a common and disabling mental disorder with complex inheritance and an estimated heritability exceeding 80%.1 Genome-wide association studies are beginning to identify common genetic variation accounting for a small fraction of the genetic risk and support the existence of a very large number of susceptibility loci.[2,3,4,5] Many studies have demonstrated a strong selective disadvantage for SZ, the patients having on average half the number of offspring than the general population,[6,7,8] yet the frequency of the disease persists high at 1%
We evaluated nine factorial phenotypes derived from a principal component phenotypic analysis of 73 indicators, which has been previously described in detail.[47]
Samplewide non-parametric linkage (NPL) scores across the genome were used to extract the scores at the location of each of the 10 genes of interest and to obtain their average, which was compared with the average scores of 100 000 random draws of 10 loci from across the genome. This method, which we have described and validated in simulated and real data, tests whether a set of loci is enriched for true linkage signals, regardless of their individual statistical significance.[49]
Summary
Schizophrenia (SZ) is a common and disabling mental disorder with complex inheritance and an estimated heritability exceeding 80%.1 Genome-wide association studies are beginning to identify common genetic variation accounting for a small fraction of the genetic risk and support the existence of a very large number of susceptibility loci.[2,3,4,5] Many studies have demonstrated a strong selective disadvantage for SZ, the patients having on average half the number of offspring than the general population,[6,7,8] yet the frequency of the disease persists high at 1%. The biological processes accomplishing these tasks might be robust and tolerate mildly damaging variation, it is possible that accumulation of such variation in components of the same process, either by new mutation or by co-inheritance, can lead to significant neurodevelopmental defects and SZ. Single deleterious mutations would be quickly cleared by selection, mildly deleterious variants that aggregate to cause disease would be resistant to selection because as their frequency becomes lower, their rate of co-occurrence is reduced exponentially and in most carriers they do not lead to a selective disadvantage
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