A polygenic burden of rare disruptive mutations in schizophrenia

By Shaun Purcell, J. Moran, Menachem Fromer, D. Ruderfer, N. Solovieff, P. Roussos, C. O’Dushlaine, K. Chambert, Sarah L Bergen, A. Kähler and 22 more. 2014

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Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.

Subfields: Genetics, Molecular Biology

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Citations in the corpus

Modelling learning and memory in Drosophila to understand Intellectual Disabilities. (2020, positive): “CYFIP1 has emerged as a significant risk factor for SCZ and ASDs (Tam et al., 2010; Leblond et al., 2012; Zhao et al., 2013; Purcell et al., 2014; Stefansson et al., 2014; Waltes et al., 2014; Vanlerberghe et al., 2015; Wang et al., 2015; Butler, 2017; Williams et al., 2020).”
The Evaluation of Tools Used to Predict the Impact of Missense Variants Is Hindered by Two Types of Circularity (2015, background): “Current high-throughput techniques to investigate the genetic basis of inherited diseases yield large numbers of potentially pathogenic sequence alterations [Tennessen et al., 2012; Purcell et al., 2014].”
Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia (2016, background): “The 109 available data are incomplete but implicate synaptic components, including calcium channel 110 subunits and post-synaptic elements (5, 7-9).”