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

Sci Rep. 2018 May 2;8(1):6915. doi: 10.1038/s41598-018-25280-4.

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.

Publication types

  • Multicenter Study

MeSH terms

  • Adult
  • Case-Control Studies
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Genome-Wide Association Study*
  • Humans
  • Lipid Metabolism / genetics
  • Lipids / biosynthesis
  • Lipogenesis / genetics
  • Loss of Function Mutation
  • Myelin Sheath / genetics*
  • Myelin Sheath / metabolism
  • Open Reading Frames
  • Polymorphism, Single Nucleotide
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism
  • Sweden

Substances

  • Lipids