Genome sequencing broadens the range of contributing variants with clinical implications in schizophrenia

Abstract

The range of genetic variation with potential clinical implications in schizophrenia, beyond rare copy number variants (CNVs), remains uncertain. We therefore analyzed genome sequencing data for 259 unrelated adults with schizophrenia from a well-characterized community-based cohort previously examined with chromosomal microarray for CNVs (none with 22q11.2 deletions). We analyzed these genomes for rare high-impact variants considered causal for neurodevelopmental disorders, including single-nucleotide variants (SNVs) and small insertions/deletions (indels), for potential clinical relevance based on findings for neurodevelopmental disorders. Also, we investigated a novel variant type, tandem repeat expansions (TREs), in 45 loci known to be associated with monogenic neurological diseases. We found several of these variants in this schizophrenia population suggesting that these variants have a wider clinical spectrum than previously thought. In addition to known pathogenic CNVs, we identified 11 (4.3%) individuals with clinically relevant SNVs/indels in genes converging on schizophrenia-relevant pathways. Clinical yield was significantly enriched in females and in those with broadly defined learning/intellectual disabilities. Genome analyses also identified variants with potential clinical implications, including TREs (one in DMPK; two in ATXN8OS) and ultra-rare loss-of-function SNVs in ZMYM2 (a novel candidate gene for schizophrenia). Of the 233 individuals with no pathogenic CNVs, we identified rare high-impact variants (i.e., clinically relevant or with potential clinical implications) for 14 individuals (6.0%); some had multiple rare high-impact variants. Mean schizophrenia polygenic risk score was similar between individuals with and without clinically relevant rare genetic variation; common variants were not sufficient for clinical application. These findings broaden the individual and global picture of clinically relevant genetic risk in schizophrenia, and suggest the potential translational value of genome sequencing as a single genetic technology for schizophrenia.

Fig. 1. Schematic representation of the identified contributions of rare high-impact variants with potential clinical implications to schizophrenia.

The overall “doughnut” graph indicates the study design that included 26 individuals (Supplementary Table S2) with pathogenic/likely pathogenic rare copy number variants (CNVs; blue sections, including five with other reported genetic risk factors indicated by blue checkered overlay). Red sections indicate the total 17 individuals identified to have other types of rare high-impact variants proposed to have potential clinical relevance for schizophrenia; 14 of these, representing 6% of individuals without pathogenic CNVs, are also shown with detailed breakdown of variant types in a bar graph on the right. This shows nine individuals with rare SNVs/indels, and three with CTG tandem repeat expansions (TREs), deemed to have potential clinical implications; also shown are two individuals with ultra-rare LoF variants in ZMYM2, proposed here as a putative schizophrenia-candidate gene. One other individual with an ultra-rare LoF variant in ZMYM2, and two individuals with clinically relevant rare SNVs/indels (Tables 1, 3), also had a pathogenic CNV (blue checkered overlay on red section of doughnut graph). Also shown (yellow sections) are 16 individuals belonging to the top twentieth percentile of schizophrenia-PRS (Supplementary Fig. S7); note that schizophrenia-PRS has not yet reached proposed clinical relevance.

Fig. 2. Genetic risk for schizophrenia and clinical/demographic variables.

This figure shows results for analyses of five clinical variables/features (family history of schizophrenia/psychosis, ID, early age at onset, mild syndromic features, and biological sex) with respect to rare clinically relevant variant burden, defined as the number of CNVs and/or SNVs/indels per individual. Orange and blue coloured boxes, and vertical bars representing 95% confidence intervals, indicate respectively results for individuals with and without each of the five variables; numbers for each subgroup are indicated in brackets under variable labels (Supplemental Table S5), and p-values for analyses are provided above graphed results. Clinically relevant rare variant burden was significantly greater for females, individuals with broadly defined ID, or with mild syndromic features.