A polygenic burden of rare disruptive mutations in schizophrenia

In the citing paper

“These findings support our model in which CYFIP1 regulation of calcium channel subunits compromise intracellular calcium levels, resulting in delayed axonal development10,84,85 (Fig. 7).”

In the citing paper

“Additionally, a polygenic pattern including a rare heterozygous disruptive nonsense variant, p.Arg624Ter, in CYFIP1 was detected in a patient diagnosed with SCZ115 (Table 2n).”

In the citing paper

“direct comparisons of the contributions of common and rare genetic variation show that common variation dominates heritable risk for SCZ and ASD (Gaugler et al., 2014; Purcell et al., 2014)”

In the citing paper

“In the instances where this has been studied directly, polygenic risk acts additively with major mutational burdens (Gaugler et al., 2014; Niemi et al., 2018; Purcell et al., 2014; Weiner et al., 2017).”

In the citing paper

“Thus, many severe mutations do not converge on one specific phenotype but instead seem to cause a range of clinical disorders74,76,80,81,84,87,91.”

In the citing paper

“Additionally, whole-exome sequencing studies of other neurodevelopmental disorders have found enrichment for FMRP targets in rare mutations in schizophrenia81, intellectual disability68 and epilepsy78.”

In the citing paper

“Earlier schizophrenia sequencing studies have established that ultra-rare and de novo mutations contribute to risk as a category, and have prioritized disease-relevant tissues and processes, specifically observing an enrichment in neuronal genes and synaptic processes9,11,19–23.”

In the citing paper

“among 5,092 (of the 12,332) individuals who were also part of an earlier sequencing study9, the additional data allowed us to re-classify ~66% of variants that had been “singletons” as segregating variants (not URVs in the current analysis).”

In the citing paper

“A strong and consistent finding in exome-sequencing studies of schizophrenia involves an excess of variants in genes whose mRNAs are bound by the fragile X mental retardation protein (FMRP)9,12,27.”

In the citing paper

“The observed enrichment was consistent across data from previously analyzed exomes9 and newly generated data (Supplementary Fig. 5); as the previously analyzed exomes were sequenced across randomized batches with equal number of cases and controls in each batch, this provides additional evidence that the enrichment is not due to technical effects.”

In the citing paper

“The fact that an analysis of the current scale (4,877 cases, 6,203 controls, and 45,376 other genomes used to help identify ultra-rare variants) did not implicate individual genes of large effect in an unbiased exome-wide search – while documenting a very clear exome-wide elevation of hundreds of pathogenic variants across 4,877 individuals affected with schizophrenia relative to controls – lends”

In the citing paper

“Psychiatric cases with a diagnosis of schizophrenia or bipolar disorder were ascertained from the Swedish National Hospital Discharge Register as described in previous studies9,50, which captures all inpatient hospitalizations. Controls were randomly selected from population registers.”

In the citing paper

“SCZ is truly complex and appears to result from a myriad of genetic variants exerting small effects on disease risk4,5, conforming closely to a classical polygenic model.”

In the citing paper

“SCZ is truly complex and appears to result from a myriad of genetic variants exerting small effects on disease risk4,5, conforming closely to a classical polygenic model.”

In the citing paper

“The available data are incomplete but implicate synaptic components, including calcium channel subunits and post-synaptic elements5–7.”

In the citing paper

“We note that strong, independent support of our findings comes from the observation that analyses of rare variants have also implicated postsynaptic pathways in SCZ etiology23,24, suggesting that both rare and common variants are relevant.”