De Novo Mutation in Schizophrenia

Abstract

Several studies in the last 5 years have shown that newly arising (de novo) mutations contribute to the genetics of schizophrenia (SZ). This will replenish genetic variants removed by natural selection and could, in part, explain why SZ prevalence has remained stable in the general population despite low fecundity. The strongest evidence to date for the association between SZ and de novo mutation comes from studies of de novo copy number variation (CNV), where the rate of de novo CNV mutation is shown to be increased in cases when compared with controls, and genes disrupted by these mutations are enriched for those encoding proteins involved in synaptic function and development. Previous estimates have shown high levels of negative selection operating against SZ associated CNVs, and we provide an updated estimate of these levels of selection using the most recently published data. Recent studies involving next-generation sequencing technology have provided preliminary evidence that de novo single-nucleotide mutations might also increase risk of SZ. However, these are very small in scale, and the results can only be considered as preliminary.

Positive Traits in the Bipolar Spectrum: The Space between Madness and Genius

“…While the mutation rate is low, the overall target size is large, involving many genes and regulatory regions. This model fits well with the apparent impact of rare structural and de novo variants on schizophrenia susceptibility [146,147,148,149,150,151,152], the reported effects of paternal age [153], and with the severe fertility disadvantages that have been observed in schizophrenia [154,155,156]. While structural variants do not appear to contribute significantly to risk for bipolar disorder, rare variants may play a role [157,158,159,160].…”

“…This appears contrary to evolution theory, in which genetic variants associated with a loss of fitness are presumably pruned from the gene pool through the process of natural selection [143,144]. Some have suggested that psychiatric illnesses result from polygenic mutation-selection balance, whereby genetic variants that reduce fitness are introduced through mutation and pruned from the gene pool at a rate proportional to their adverse effects on fitness [143,144,145,146,147]. While the mutation rate is low, the overall target size is large, involving many genes and regulatory regions.…”

An adaptationist perspective on the etiology of depression

“…One cause of malfunction, genetic mutation, has been associated with several mental illnesses. An increased mutation rate, for example caused by maternal famine (McClellan et al, 2006) or greater paternal age (Crow, 2003;Kong et al, 2012;Sipos et al, 2004), has been associated with increased risk of schizophrenia (Ionita-Laza et al, 2014;Rees et al, 2012;Xu et al, 2008), autism (Durkin et al, 2008;O'Roak et al, 2012;Reichenberg et al, 2006), other developmental disorders (Vissers et al, 2010), and bipolar disorder (Frans et al, 2008). While many studies have identified alleles associated with depression, to our knowledge no study has shown an association between increased mutation rate and MDD.…”

Beta-catenin in schizophrenia: Possibly deleterious novel mutation

“…Etiological factors, resulting in schizophrenia, are in fact mostly genetic, making up to 80% of all factors contributing to the pathogenesis (Sullivan et al, 2003). Apart from long-established linkage and association studies of schizophrenia genetics, more approaches have emerged, studying de novo copy number variations and point mutations by next-generation sequencing (reviewed in Rees et al, 2012;Rodriguez-Murillo et al, 2012;Schreiber et al, 2013;Escudero and Johnstone, 2014;Kavanagh et al, 2015). Despite the complexity of schizophrenia genetics, the genetic studies are advancing, leading to discovery of numerous candidate genes, whose role was confirmed by different studies, important mostly in neural development, neurotransmission and immune system (Rodriguez-Murillo et al, 2012;Fromer et al, 2014;Hall et al, 2015).…”