Genome-Wide Association Studies (GWAS) as a Strategy for Exploring Genetics of Common Diseases
Most of the differences between individual copies of the human genome are due to common alleles of Single Nucleotide Polymorphisms (SNPs). During the course of the Human Haplotype Map (HapMap) project, we observed that whole genome arrays of hundreds of thousands of SNPs can amply represent almost all common genetic variation in humans (Pe'er et al. 2006). The community of human geneticists is now using this infrastructure to associate these variants to traits by examination of genotypes and phenotypes in large cohorts. We are involved in the analysis of several such GWAS datasets across multiple phenotypes, each with a unique computational challenge requiring method development.
GWAS of schizophrenia in European Americans and African Americans
The Genetic Analysis Information Network (GAIN) is a chain of GWA studies executed with coordinated genotyping and oversight. Together with collaborators Frank Dudbridge and Peter Holmans we are part of the analysis team for the GAIN study of schizophrenia, spearheaded by Doug Levinson and Pablo Gejman. The study includes >5000 European American and >2200 African American samples, approximately equally split between cases and controls, all typed by the Affymetrics SNP6.0 array. In addition to the usual challenges in the genetics of schizophrenia - small effects of each locus and effects by harder-to-measure copy number variants - the combination of multiple populations, specifically the admixed African American population, all require fine tuned analysis.
GWAS of Severe Adverse Effects of Commonly Used Drugs
GWA studies aim at both exposing key molecular-level players in disease processes as well as providing diagnostic value. The latter is emphasized in pharmacogenetic studies, specifically in studies of adverse effects. Severe adverse effects are rare, but often life threatening reactions, often shared by multiple drugs. This motivates coalescing small cohorts from many sources, and indeed the Severe Adverse Effects Consortium brings together 10 big pharmaceutical companies to study such events with pooled samples and resources. Columbia is the main academic partner, providing a home for the data and analyzing association. A major challenge in SAEC data has to do with the limited sample size of the case population for these rare phenotypes.
GWAS of Metabolic Syndrome in the entire adult population of the
A model system where complete genetics can be practiced at present is a small, isolated population. In such a place everybody can genotyped for the markers along entire genome, and because of the bottleneck effect on gene flow during founding of the population, markers would exhibit high correlation to disease-causing variants, therefore the marker density offered by current technology has the potential of dissecting the genetics of heritable disease.
The Pacific island of Kosrae, Federates States of Micronesia is exactly such a population. Furthermore, high prevalence of the diabetes, obesity, hypertension and dislipidemia make the island a compelling population to dissect the genetics of their combination, the Metabolic Syndrome. Joint with labs of Jeff Friedmann and Jan Breslow at the Rockefeller Institute, Marcus Stoffel at and the Altshuler / Daly groups at Broad Institute we have quantified the effects of population isolation in Kosrae, and mapped European admixture into the island. We have recently generated genomewide data for essentially the entire adult population, making an association study for metabolic disorders of unprecedented magnitude and complexity.
We are continually developing computational methods to handle the complexities of the Kosrae data and other special populations in terms of magnitude, population isolation, internal family relatedness, and ethnic admixture.
GWAS and Systems' Biology of Parkinson's Disease in Ashkenazi Samples
Parkinson's Disease (PD) have been tough to crack by genetic association in general population. However, in the Ashkenazi population two genes are known to have common functional variants: LRRK2 and GBA. We intend to use this advantage to conduct a GWAS for PD in Ashkenazim, collected by our collaborators from Tel Aviv, Avi Orr and Nir Giladi.