Psychiatric Genetics

Introduction

Schizophrenia (SCZ) and bipolar affective disorder (BPAD) are severe, disabling psychiatric illnesses that feature prominently in the top ten causes of disability world wide. Research into the causes of these devastating disorders and the development of improved interventions is a high scientific, social, individual and public health priority.

As yet, little is known with any certainty about their cellular and molecular basis, but family, twin and adoption studies indicate that, although inheritance patterns are complex, major psychiatric illness has a significant genetic component. For example, the risk to a first-degree relative of an affected person is increased tenfold over that of the general population and several chromosomal regions that are likely to harbour susceptibility genes for these disorders have been identified. Family, twin and adoption studies have also shown that there is a genetic relationship between different psychiatric phenotypes, implying that some genetic risk factors may contribute to a range of psychotic symptoms, and give rise to phenotypes that cross the traditional diagnostic boundaries of SCZ and affective disorders.

Research

Our work aims to identify gene variants that increase susceptibility to SCZ and BPAD. The mode of inheritance of the major psychoses is complex, demonstrating incomplete penetrance, and, in all likelihood, extensive locus heterogeneity and oligo or polygenicity. A prevailing genetic model for psychosis is a quantitative trait locus (QTL) model that invokes the interaction of several genes of small effect. However, in common with other complex disorders including breast cancer, colon cancer, diabetes and Alzheimer's disease, there is also growing evidence that psychosis can arise from the inheritance of mutations with large effect and strong genotype-phenotype correlations (a quasi-Mendelian subset).

There is support for a quasi-Mendelian subset in the psychoses from extended pedigree studies. For example, in BPAD significant linkage has been reported in extended pedigrees on chromosomes 1q, 4p, 4q, 12q, 18q, 21q (Potash and DePaulo, 2000).. These types of study have been criticised because of inconsistent replications in genome scans of affected sibling pairs or large collections of small families. Failure to replicate could be due to lack of power of existing sample sets to detect alleles of small effect, and/or to the presence of substantial locus heterogeneity.

Thus it remains to be determined where the balance lies between the models of Mendelian inheritance with genetic heterogeneity and a fully quantitative model. However, it is exciting that for the first time, we have access to both adequate technology and well-documented sample sets with which to rigorously test and compare these alternative models.

Approaches

We take two main approaches to the initial identification of susceptibility loci. The first involves the identification and analysis of genes affected by chromosomal rearrangements, such as translocations and deletions. The second involves linkage analysis of pedigrees where psychiatric illness segregates as a quasi-Mendelian trait. All of this work is carried out via a long-standing collaboration with Prof Douglas Blackwood and Dr Walter Muir at the Dept. of psychiatry of Edinburgh) who provide clinical expertise and access to biological samples from families, parent offspring trios and case control samples.

WTCRF Genetics Core

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