Analyses of rare and common alleles in parent-proband trios implicate rare missense variants in SLC6A1 in schizophrenia and confirm the involvement of loss of function intolerant and neurodevelopmental disorder genes

Abstract

Schizophrenia is a highly polygenic disorder with important contributions coming from both common and rare risk alleles, the latter including CNVs and rare coding variants (RCVs), sometimes occurring as de novo variants (DNVs). We performed DNV analysis in whole exome-sequencing data obtained from a new sample of 613 schizophrenia trios, and combined this with published data for a total of 3,444 trios. Loss-of-function (LoF) DNVs were significantly enriched among 3,488 LoF intolerant genes in our new trio data (rate ratio (RR) (95% CI) = 2.23 (1.31, 3.79); p = 2.2 × 10−3), supporting previous findings. In the full dataset, genes associated with neurodevelopmental disorders (NDD; n=160) were significantly enriched for LoF DNVs (RR (95% CI) = 3.32 (2.0, 5.21); p = 7.4 × 10−6). Within this set of NDD genes, SLC6A1, encoding a gamma-aminobutyric acid transporter, was associated with missense-damaging DNVs (p = 5.2 × 10−5). Using data from a subset of 1,122 trios for which we had genome-wide common variant data, schizophrenia polygenic risk was significantly over-transmitted to probands (p = 2.6 × 10−60), as was bipolar disorder common variant polygenic risk (p = 5.7 × 10−17). We defined carriers of candidate schizophrenia-related DNVs as those with LoF or deletion DNVs in LoF intolerant or NDD genes. These individuals had significantly less over-transmission of common risk alleles than non-carriers (p = 3.5 × 10−4), providing robust support for the hypothesis that this set of DNVs is enriched for those related to schizophrenia.

De novo variation in bipolar disorder

“…While the success of GWAS have led to the successful discovery of common variants in complex disorders, the study of rare variants, and specifically, de novo variants, has primarily focused on early onset neurodevelopmental disorders such as intellectual disability [ 12 ], and autism [ 41 , 54 ], where the combination of large samples sizes and a more restricted mutational target have led to the discovery of numerous robustly associated genes and genesets. In schizophrenia, de novo studies have led to the identification of the chromatin remodeling gene SETD1A [ 16 ], although most of the observed enrichment has been found at the level of genesets [ 14 , 15 ]. Our results appear most consistent with findings from schizophrenia, suggesting the presence of enriched variants within gene-sets that show cross-disorder associations.…”

Genetics of Childhood-onset Schizophrenia 2019 Update

“…Furthermore, the elevated burden of common schizophrenia risk alleles in patients who also carry risk CNVs was found to be inversely proportional to the effect size of the risk CNV 57 . Similarly, schizophrenia patients with damaging de novo variants in genes that are intolerant to mutation or are associated with neurodevelopmental disorders more broadly, were found to have lower transmission of schizophrenia PRS from parents compared to patients without de novo variants in these genes 58 .…”

Novel Approaches for Identifying the Molecular Background of Schizophrenia

“…If causal variations that slightly alter the expression of target genes in the brain can result in moderate increases in schizophrenia risk, then mutations that radically alter the structures or expression levels of these target genes could have greater penetrance and lead to more severe brain dysfunction [16,47,48]. Several genes, out of hundreds identified within a few hundred kb from GWAS hits (in GWAS region neighbourhoods, hereafter referred to as 'GWAS RN') have been associated with monogenic syndromes, with symptoms such as mental retardation, impaired socialization, and epilepsy.…”

“…If exome comparison indicates that mutations in a gene within the GWAS RN can be disease-causing, then the expression of that gene may be influenced by the common causal variant associated with the disease. For schizophrenia, only 3 genes, rare mutations in which significantly increase disease risk have been so far identified, including SETB1A [48], RBM12 [52], and SLC6A1, which encodes one of the γ-aminobutyric acid (GABA) transporters [16]. SLC6A1 is located just near a GWAS region, approximately 200 thousand bp away from its boundary, indicating that the causal variant in this GWAS region likely affects the expression of SLC6A1 (Figure 1D).…”

“…Genes, identified using three different approaches of this class as being schizophrenia genes, are represented. Whole-exome sequencing (WES) studies indicated that rare mutations in SLC6A1 cause schizophrenia [16]. This strongly suggests that expression of SLC6A1 is regulated by schizophrenia-associated common variants as one of GWAS regions is located in close vicinity to this gene (200 kb upstream).…”