Pathomechanisms and Signatures in the Longitudinal Course of Psychosis



064_ The genetic burden of rare and potentially damaging variants in the schizophrenia risk-locus Xq28,distal

Research Question and Aims

Specific copy number variations (CNVs), deletions and duplications, are well-established risk factors for schizophrenia (SCZ). The world´s largest CNV analysis for SCZ to date published by the Psychiatric Genomics Consortium provided suggestive evidence for the first risk-associated locus on the X-chromosome: rare duplications in Xq28,distal confer risk to SCZ in both genders and span eight different genes. Due to shared genomic breakpoints of the duplications, it is unclear which gene/genes in this locus is/are relevant for the phenotype. As we focus on rare and potentially damaging variants, we aim to increase the samples size by including around 200 cases with SCZ of the PsyCourse cohort in our analyses. The identification of an increased burden of rare and potentially damaging variants in the case compared to the control cohort in any of the implicated gene/s will be additional evidence for the involvement of this gene/s in the pathogenesis of SCZ.

Analytic Plan

The working hypothesis is that genes relevant for the phenotype will be enriched for rare and potentially damaging variants in the case compared to the control cohort. Therefore, all coding regions of the implicated genes are sequenced in 1935 patients with SCZ and 1905 population-based controls using the single molecule molecular inversion probe (smMIP) method on an Illumina HiSeq 2500. Quality control is performed in two steps. First, SNP-Array data is used to asses gender mismatches, relatedness and population stratification. Secondly, the smMIP sequencing data is analysed to evaluate the coverage, heterozygous/homozygous (het/hom) - and transversion/transition (ti/tv) - ratios. After applying the GATK hard filter criteria, we filter for rare and potentially damaging non-synonymous (missense, stopgain stoploss, startloss) single nucleotide variants and Indels with 1. a minor allele frequency (MAF) ≥ 0,1% in our study cohort or according the frequency data for the non-psych, non-Finnish Europeans provided by the Exome Aggregation Consortium (ExAC) and 2. a Combined Annotation Dependent Depletion (CADD) score ≥ 20. In order to identify an increased burden of rare and potentially damaging variants, the statistical analysis is performed in a gene-wise manner using the X-chromosomal model of the Optimal Unified Sequence Kernel Association (SKAT-O) test with gender as a covariate.

Resources needed

Sex: v1_sex
DSM-IV: v1_scid_dsm_dx_cat “Schizophrenia”
Genotype-Data: character, psyc_id
Ethnicity: v1_cntr_brth