Oligogenic rare variant contributions in schizophrenia and their convergence with genes harbouringde novomutations in schizophrenia, autism and intellectual disability: Evidence from multiplex families

Abstract

Clinical and genetic heterogeneity has been documented extensively in schizophrenia, a common behavioural disorder with heritability estimates of about 80%. Common and rare de novo variant based studies have provided notable evidence for the likely involvement of a range of pathways including glutamatergic, synaptic signalling and neurodevelopment. To complement these studies, we sequenced exomes of 11 multimember affected schizophrenia families from India. Variant prioritisation performed based on their rarity (MAF <0.01), shared presence among the affected individuals in the respective families and predicted deleterious nature, yielded a total of 785 inherited rare protein sequence altering variants in 743 genes among the 11 families. These showed an enrichment of genes involved in the extracellular matrix and cytoskeleton components, synaptic and neuron related ontologies and neurodevelopmental pathways, consistent with major etiological hypotheses. We also noted an overrepresentation of genes from previously reported gene sets with de novo protein sequence altering variants in schizophrenia, autism, intellectual disability; FMRP target and loss of function intolerant genes. Furthermore, a minimum of five genes known to manifest behavioural/neurological and nervous system abnormalities in rodent models had deleterious variants in them shared among all affected individuals in each of the families. Majority of such variants segregated within and not across families providing strong suggestive evidence for the genetically heterogeneous nature of disease.More importantly, study findings unequivocally support the classical paradigm of cumulative contribution of multiple genes, notably with an apparent threshold effect for disease manifestation and offer a likely explanation for the unclear mode of inheritance in familial schizophrenia.Polyphen2_HDIV, Polyphen2_HVAR, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, MetaSVM, M-CAP and fathmm-MKL_coding and CADD scaled score =>15; or CADD scaled score>=10 and <15 but predicted to be damaging by at least two different software listed above) for further analysis. All these tools were part of Kggseq (Li et al., 2012). All these variants are henceforth referred to as "deleterious shared variants".

Structural variation and eQTL analysis in two experimental populations of chickens divergently selected for feather-pecking behavior

“…In schizophrenia and bipolar disorder, the prefrontal cortical expression of PPP1R9A was altered [70] and its gene product Neurabin regulates anxiety-like behavior in adult mice [71]. INPP4A has been implicated in multiple neurological conditions, namely schizophrenia, autism, epilepsy, and intellectual disability [72][73][74]. An additional link to schizophrenia is a frameshift variant in the GPATCH8 gene in exon 9 of transcript GPATCH8-201 (Table 3), an ortholog of ZNF804A, which has been shown to impact various mental illnesses via pre-mRNA processing [75].…”

Structural variation and eQTL analysis in two experimental populations of chickens divergently selected for feather pecking behavior

“…In schizophrenia and bipolar disorder, the prefrontal cortical expression of PPP1R9A was altered [57] and its gene product Neurabin regulates anxiety-like behavior in adult mice [58]. INPP4A has been implicated in multiple neurological conditions, namely schizophrenia, autism, epilepsy, and intellectual disability [59][60][61]. An additional link to schizophrenia is a frameshift variant in the GPATCH8 gene in exon 9 of transcript GPATCH8-201 (Table 3), an ortholog of ZNF804A, which has been shown to impact various mental illnesses via pre-mRNA processing [62].…”