The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability

Abstract

By performing a meta-analysis of rare coding variants in whole-exome sequences from 4,133 schizophrenia cases and 9,274 controls, de novo mutations in 1,077 family trios, and copy number variants from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare, damaging variants in 3,488 genes previously identified as having a near-complete depletion of loss-of-function variants. In patients with schizophrenia who also have intellectual disability, this burden is concentrated in risk genes associated with neurodevelopmental disorders. After excluding known risk genes for neurodevelopmental disorders, a significant rare variant burden persists in other genes intolerant of loss-of-function variants; although this effect is notably stronger in patients with both schizophrenia and intellectual disability, it is also seen in patients with schizophrenia who do not have intellectual disability. Together, our results show that rare, damaging variants contribute to the risk of schizophrenia both with and without intellectual disability and support an overlap of genetic risk between schizophrenia and other neurodevelopmental disorders.

Figure 1

Analysis workflow. Data sets are shown in blue, statistical methods and analysis steps are shown in green, and results (figures and tables) from the analysis are shown in orange. A: Enrichment analyses in 1,766 gene sets using the entire rare variant data set. B: Enrichment analyses in LoF intolerant and developmental disorder genes in the subset of cases with information on cognitive function. ID: intellectual disability; SCZ: schizophrenia; SCZ-ID: schizophrenia patients with intellectual disability.

Figure 2

Enrichment of schizophrenia rare variants in genes intolerant of loss-of-function variants. A: Schizophrenia cases compared to controls for rare SNVs and indels; B: Rates of de novo mutations in schizophrenia probands compared to control probands; C: Case-control CNVs. P-values shown were from the test of LoF enrichment in A, LoF enrichment in B, and all CNVs enrichment in C. Error bars represent the 95% CI of the point estimate. LoF intolerant: 3,448 genes with near-complete depletion of truncating variants in the ExAC database; Rest: the remaining genes in the genome with pLI < 0.9; Damaging missense: missense variants with CADD phred > 15. Asterisk: P < 1 x 10^-3.

Figure 3

Enrichment of rare loss-of-function variants in LoF intolerant genes in schizophrenia cases stratified by information on cognitive function compared to controls. The P-values shown were calculated using the variant threshold method comparing LoF burden between the corresponding cases and controls. Error bars represent the 95% CI of the point estimate. Damaging missense: missense variants with CADD phred > 15.

Figure 4

Enrichment of rare loss-of-function variants in known severe developmental disorder genes in schizophrenia cases stratified by information on cognitive function compared to controls. The P-values shown were calculated using the variant threshold method comparing LoF burden between the corresponding cases and controls. Error bars represent the 95% CI of the point estimate. Damaging missense: missense variants with CADD phred > 15.