High-density genotyping analysis of complex mental illness
Purpose: Few whole genome linkage or candidate gene studies have yielded results about major mental disorders that generalize to multiple populations. One factor contributing to this has been the previously limited power of the techniques. Recent advances make it possible to rapidly perform highly-informative whole genome linkage, family-based association, and case-control association analyses. Each of these approaches has its own strengths and weaknesses, but taken together, results from an integrated analysis can implicate promising novel candidate genes. Here, we provide an overview of the integrated methodology that we have used on DNA samples from subjects with schizophrenia and bipolar disorder living in two Portuguese island groups – the Azores and Madeiran islands.
Methods: We genotyped approximately 400 subjects from 55 multiplex pedigrees with schizophrenia and 40 pedigrees with bipolar disorder using high density genotyping arrays with probes for nearly 300,000 SNPs. In parallel, we genotyped 100 familial cases of schizophrenia, 100 familial cases of bipolar disorder, and 100 screened controls on a total of 500,000 SNPs for a case-control study. In the families, haplotype-based non-parametric and parametric linkage were used to define candidate gene regions, along with family-based association to test for over transmission of haplotypes. In the case-control study, both singlepoint and haplotype-based association analyses were used.
Results: Each method yielded many significant results. However, when the results were combined, only a small number of specific haplotypes and genes were implicated by more than one approach.
Conclusions: It is now possible to combine high-throughput genetic data from multiple approaches to achieve new insights into the potential biological basis for major mental disorders. The potential of this combined approach is greater than that of any single mode of discovery for complex genetic diseases.