A polygenic burden of rare disruptive mutations in schizophrenia

Abstract

By analyzing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we have demonstrated a polygenic burden primarily arising from rare (<1/10,000), disruptive mutations distributed across many genes. Especially enriched genesets included the voltage-gated calcium ion channel and the signaling complex formed by the activity-regulated cytoskeleton-associated (ARC) scaffold protein of the postsynaptic density (PSD), sets previously implicated by genome-wide association studies (GWAS) and copy-number variation (CNV) studies. Similar to reports in autism, targets of the fragile × mental retardation protein (FMRP, product of FMR1) were enriched for case mutations. No individual gene-based test achieved significance after correction for multiple testing and we did not detect any alleles of moderately low frequency (~0.5-1%) 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.

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…IRSp53 has been implicated also in other psychiatric disorders, including ADHD (attention deficit/hyperactivity disorder) 207,208 and schizophrenia 209,210 . Overexpression of IRSp53 in cultured neurons increases the density of dendritic spines without affecting spine length or width.…”

No evidence for rare recessive and compound heterozygous disruptive variants in schizophrenia

“…Additional detail on sample ascertainment and sequence data generation has been previously published. 8 BAM and VCF files are available in the dbGaP study phs000473.v1 (http://www.ncbi.nlm.nih.gov/ projects/gap/cgi-bin/study.cgi?study_id = phs000473.v1.p1).…”

“…Recently, large-scale exome-sequencing studies have searched for rare variants that strongly increase risk, 8,9 although the relatively high baseline rate of rare neutral coding variation makes this challenging. 10 To focus on rare variants that are a priori more likely to be highly penetrant for disease, one approach is to study de novo mutations, as these are effectively uncensored by selection pressures.…”

“…Here we apply both approaches in a large Swedish population-based sample 8,16 of SCZ cases and controls: we first test the recessive model indirectly by comparing the SNP-derived ROH burden in cases versus controls, and second, we use exome sequencing to assess directly the burden of complete knockout variants.…”

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

“…Examination of the cumulative effects of inheriting multiple risk alleles—each of which are significantly or nominally associated with disease risk—has been able to powerfully differentiate groups of cases from controls in independent population‐based studies [Purcell et al, 2014, 2009; Patel et al, 2010; Ayalew et al, 2012; Terwisscha van Scheltinga et al, 2012]. However, despite phenotypic aggregation within families [McGuffin et al, 2003; Lichtenstein et al, 2009], no studies have so far examined polygenic risk incorporating these common genetic factors in a family context in adults, with only one group to date reporting on polygenic risk in adolescent offspring of individuals with BP [Whalley et al, 2012, 2013].…”