Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder

Abstract

Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders with overlapping susceptibility loci and symptomatology. We conducted a genome-wide association study (GWAS) of these disorders in a large Swedish sample. We report a new and independent case–control analysis of 1507 SCZ cases, 836 BD cases and 2093 controls. No single-nucleotide polymorphisms (SNPs) achieved significance in these new samples; however, combining new and previously reported SCZ samples (2111 SCZ and 2535 controls) revealed a genome-wide significant association in the major histocompatibility complex (MHC) region (rs886424, P = 4.54 × 10−8). Imputation using multiple reference panels and meta-analysis with the Psychiatric Genomics Consortium SCZ results underscored the broad, significant association in the MHC region in the full SCZ sample. We evaluated the role of copy number variants (CNVs) in these subjects. As in prior reports, deletions were enriched in SCZ, but not BD cases compared with controls. Singleton deletions were more frequent in both case groups compared with controls (SCZ: P = 0.003, BD: P = 0.013), whereas the largest CNVs (>500 kb) were significantly enriched only in SCZ cases (P = 0.0035). Two CNVs with previously reported SCZ associations were also overrepresented in this SCZ sample: 16p11.2 duplications (P = 0.0035) and 22q11 deletions (P = 0.03). These results reinforce prior reports of significant MHC and CNV associations in SCZ, but not BD.

The rs11191580 variant of the NT5C2 gene is associated with schizophrenia and symptom severity in a South Chinese Han population: evidence from GWAS

“…Prior to this research, variant rs11191580 within the NT5C2 gene had been identified to be significantly associated with SCZ susceptibility, but three GWASs conducted in Swedish or broader European populations had suggested that the T allele might increase SCZ risk. 5,8,9 Besides, the correlation between GWASsupported locus rs11191580 and SCZ risk has been replicated, but the results also showed that the T allele might increase SCZ susceptibility (OR = 1.05) in a North Chinese Han population. 7 One possible reason for this discrepancy is the genetic heterogeneity of SCZ in individuals of different ethnic groups and/or regions.…”

“…7 Two subsequent GWASs showed that rs11191580 is the risk locus of SCZ. 8,9 In 2012, a GWAS in a Swedish population observed that rs11191580 was significantly associated with SCZ susceptibility. 8 In 2013, the Cross-Disorder Group of Psychiatric Genomics Consortium indicated that locus rs11191580 conferred susceptibility to five major psychiatric disorders (including SCZ) in a European population.…”

“…8,9 In 2012, a GWAS in a Swedish population observed that rs11191580 was significantly associated with SCZ susceptibility. 8 In 2013, the Cross-Disorder Group of Psychiatric Genomics Consortium indicated that locus rs11191580 conferred susceptibility to five major psychiatric disorders (including SCZ) in a European population. 9 Nevertheless, a replication study in a Japanese population suggested that rs11191580 polymorphism in the NT5C2 gene was not associated with SCZ.…”

Investigating the Impact of a Genome-Wide Supported Bipolar Risk Variant of MAD1L1 on the Human Reward System

“…The minor allele of the single-nucleotide polymorphism (SNP) rs11764590 was significantly associated with bipolar disorder. Subsequent GWAS also found significant associations of MAD1L1 with bipolar disorder (Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium, 2011) as well as associations with both bipolar disorder and schizophrenia (Bergen et al, 2012;Ruderfer et al, 2014).…”

Genetic studies of schizophrenia: an update

“…In the early years, the search for genes involved in SCZ by linkage and candidate gene studies did not produce replicable and consistent results [10,11] . From 2009 onwards, a number of creditable candidates were identifi ed, largely by GWAS, a linkage disequilibrium-based technique designed to fi nd links between genetic variations and diseases in a homogeneous population without a [25,26,110] priori knowledge of the disease. The variants discovered by GWASs are common variants, conventionally defined as those with allele frequencies ≥1%.…”