Characterization of Single Gene Copy Number Variants in Schizophrenia

Background: Genetic studies of schizophrenia have implicated numerous risk loci including several copy number variants (CNVs) of large effect and hundreds of loci of small effect. In only a few cases has a specific gene been clearly identified. Rare CNVs affecting a single gene offer a potential avenue to discovering schizophrenia risk genes. Methods: CNVs were generated from exome sequencing of 4913 schizophrenia cases and 6188 control subjects from Sweden. We integrated two CNV calling methods (XHMM and ExomeDepth) to expand our set of single-gene CNVs and leveraged two different approaches for validating these variants (quantitative polymerase chain reaction and NanoString). Results: We found a significant excess of all rare CNVs (deletions: p = .0004, duplications: p = .0006) and single-gene CNVs (deletions: p = .04, duplications: p = .03) in schizophrenia cases compared with control subjects. An expanded set of CNVs generated from integrating multiple approaches showed a significant burden of deletions in 11 of 21 gene sets previously implicated in schizophrenia and across all genes in those sets (p = .008), although no tests survived correction. We performed an extensive validation of all deletions in the significant set of voltage-gated calcium channels among CNVs called from both exome sequencing and genotyping arrays. In total, 4 exonic, single-gene deletions were validated in schizophrenia cases and none in control subjects (p = .039), of which all were identified by exome sequencing. Conclusions: These results point to the potential contribution of single-gene CNVs to schizophrenia, indicate that the utility of exome sequencing for CNV calling has yet to be maximized, and note that single-gene CNVs should be included in gene-focused studies using other classes of variation

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies