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Genetic variation in 117 myelination-related genes in schizophrenia: Replication of association to lipid biosynthesis genes.

ABSTRACT: Schizophrenia is a serious psychotic disorder with high heritability. Several common genetic variants, rare copy number variants and ultra-rare gene-disrupting mutations have been linked to disease susceptibility, but there is still a large gap between the estimated and explained heritability. Since several studies have indicated brain myelination abnormalities in schizophrenia, we aimed to examine whether variants in myelination-related genes could be associated with risk for schizophrenia. We established a set of 117 myelination genes by database searches and manual curation. We used a combination of GWAS (SCZ_N?=?35,476; CTRL_N?=?46,839), exome chip (SCZ_N?=?269; CTRL_N?=?336) and exome sequencing data (SCZ_N?=?2,527; CTRL_N?=?2,536) from schizophrenia cases and healthy controls to examine common and rare variants. We found that a subset of lipid-related genes was nominally associated with schizophrenia (p?=?0.037), but this signal did not survive multiple testing correction (FWER?=?0.16) and was mainly driven by the SREBF1 and SREBF2 genes that have already been linked to schizophrenia. Further analysis demonstrated that the lowest nominal p-values were p?=?0.0018 for a single common variant (rs8539) and p?=?0.012 for burden of rare variants (LRP1 gene), but none of them survived multiple testing correction. Our findings suggest that variation in myelination-related genes is not a major risk factor for schizophrenia.

SUBMITTER: Stokowy T

PROVIDER: S-EPMC5931982 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Genetic variation in 117 myelination-related genes in schizophrenia: Replication of association to lipid biosynthesis genes.

Stokowy Tomasz T Polushina Tatiana T Sønderby Ida E IE Karlsson Robert R Giddaluru Sudheer S Le Hellard Stephanie S Bergen Sarah E SE Sullivan Patrick F PF Andreassen Ole A OA Djurovic Srdjan S Hultman Christina M CM Steen Vidar M VM

Scientific reports 20180502 1

Schizophrenia is a serious psychotic disorder with high heritability. Several common genetic variants, rare copy number variants and ultra-rare gene-disrupting mutations have been linked to disease susceptibility, but there is still a large gap between the estimated and explained heritability. Since several studies have indicated brain myelination abnormalities in schizophrenia, we aimed to examine whether variants in myelination-related genes could be associated with risk for schizophrenia. We ...[more]

PMID: 29720671

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Project description:ImportanceSchizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets.ObjectiveTo identify SCZ susceptibility genes.DesignWe integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1,085,772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs.SettingLinkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases.PatientsWe included 11,185 cases and 10,768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families.Main outcomes and measuresCase-control status for SCZ.ResultsReplication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P.01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89% in the combined ancestry group (sign test, P < 2.20 x 10(-16) and 93% in subjects of European ancestry only (P < 2.20 < 10(-16)). Our results supported the major histocompatibility complex region showing a3.7-fold overall enrichment of replication values of P < .01 in subjects from European ancestry. We replicated SNPs in TCF4 (P = 2.53 x 10(-10)) and NOTCH4 (P = 3.16 x 10(-7)) that are among the most robust SCZ findings. More novel findings included POM121L2 (P = 3.51 x 10(-7)), AS3MT (P = 9.01 x 10(-7)), CNNM2 (P = 6.07 = 10(-7)), and NT5C2(P = 4.09 x 10(-7)). To explore the many small effects, we performed pathway analyses. The most significant pathways involved neuronal function (axonal guidance, neuronal systems, and L1 cell adhesion molecule interaction)and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse).Conclusions and relevanceWe replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets.

Dataset Information

Genetic variation in 117 myelination-related genes in schizophrenia: Replication of association to lipid biosynthesis genes.

Publications

Genetic variation in 117 myelination-related genes in schizophrenia: Replication of association to lipid biosynthesis genes.

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