Genome Wide Association Study of Schizophrenia in Ireland

Aiden Corvin

Michael Gill, Brien Riley, Anthony O'Neill, Kenneth Kendler.

Schizophrenia (SZ) is a complex brain disorder of onset typically in early adulthood. Resultant morbidity and mortality are substantial: the disorder reduces life expectancy by ~10 years, and globally ~5% of affected individuals commit suicide. Individuals with SZ have unemployment rates of 70-80%. Approximately 1% of the adult population are affected.

SZ is substantially heritable, where expression of the disorder is likely to be dependent on the effect of multiple modest genetic effects interacting with each other and with environmental risk factors. Molecular evidence of genetic overlap with other psychotic disorders (including bipolar disorder), suggests shared underlying biology, but this is poorly understood and current therapies for SZ, which were discovered serendipitously, are only partially effective. Identifying genetic variants that alter the risk of the disorder may direct the investigator to biological pathways of aetiological relevance. This may be important for improving diagnosis, predicting illness risk and in identifying novel targets for pharmacotherapy. Genome-wide Association (GWA) studies are a powerful methodology for identifying genes contributing to complex genetic disorders. Performing a GWA analysis in this dataset will be important in identifying SZ susceptibility genes both directly and in joint analysis with other datasets. The availability of detailed CNV data on a subset of this sample will allow a comprehensive analysis of genomic variation in this sample. The detailed phenotypic information will allow:

  1. exploration of susceptibility across psychotic disorders
  2. investigation of interaction with environmental risk factors
  3. identifying impact of risk on clinical and neuropsychological indices of illness.

To perform a Genome-Wide Association (GWA) study in a large case-control psychosis sample (n=2,738 cases; n=5,200 controls). This is a scientific collaboration between groups at Trinity College Dublin (TCD) (Corvin/Gill), Virginia Commonwealth University (VCU) (Riley/Kendler), Queens University Belfast (QUB) (O’Neill) and the Wellcome Trust Case Control Consortium (WTCCC). The goals being to:

  1. Identify common genetic variants that contribute to schizophrenia (SZ) in this population.
  2. Annotate associated variants and perform systems analyses to extract pathway ‘signals’ from noise in the primary data.
  3. Perform joint analysis with copy number variation (CNV) data at 2 million-probe resolution, to comprehensively investigate common genomic variation in SZ.
  4. Analyse a broader psychoses phenotype to establish if susceptibility extends to related disorders (e.g. bipolar disorders) or maps better to specific illness dimensions (e.g. affective or psychotic symptoms) than to clinical diagnosis.
  5. Replicate primary or secondary findings in available datasets.