Author Archives: Joe Pickrell

Integrated analysis of variants and pathways in genome-wide association studies using polygenic models of disease

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Integrated analysis of variants and pathways in genome-wide association studies using polygenic models of disease

Peter Carbonetto, Matthew Stephens
(Submitted on 21 Aug 2012)

Many common diseases are highly polygenic, modulated by a large number genetic factors with small effects on susceptibility to disease. These small effects are difficult to map reliably in genetic association studies. To address this problem, researchers have developed methods that aggregate information over sets of related genes, such as biological pathways, to identify gene sets that are enriched for genetic variants associated with disease. However, these methods fail to answer a key question: which genes and genetic variants are associated with disease risk? We develop a method based on sparse multiple regression that simultaneously identifies enriched pathways, and prioritizes the variants within these pathways, to locate additional variants associated with disease susceptibility. A central feature of our approach is an estimate of the strength of enrichment, which yields a coherent way to prioritize variants in enriched pathways. We illustrate the benefits of our approach in a genome-wide association study of Crohn’s disease with ~440,000 genetic variants genotyped for ~4700 study subjects. We obtain strong support for enrichment of IL-12, IL-23 and other cytokine signaling pathways. Furthermore, prioritizing variants in these enriched pathways yields support for additional disease-association variants, all of which have been independently reported in other case-control studies for Crohn’s disease.

Population genomics of the Wolbachia endosymbiont in Drosophila melanogaster

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Population genomics of the Wolbachia endosymbiont in Drosophila melanogaster

Mark F. Richardson, Lucy A. Weinert, John J. Welch, Raquel S. Linheiro, Michael M. Magwire, Francis M. Jiggins, Casey M. Bergman
(Submitted on 25 May 2012 (v1), last revised 2 Aug 2012 (this version, v2))

Wolbachia are maternally-inherited symbiotic bacteria commonly found in arthropods, which are able to manipulate the reproduction of their host in order to maximise their transmission. Here we use whole genome resequencing data from 290 lines of Drosophila melanogaster from North America, Europe and Africa to predict Wolbachia infection status, estimate cytoplasmic genome copy number, and reconstruct Wolbachia and mtDNA genome sequences. Complete Wolbachia and mitochondrial genomes show congruent phylogenies, consistent with strict vertical transmission through the maternal cytoplasm and recurrent loss of Wolbachia in multiple populations. Bayesian phylogenetic analysis reveals that the most recent common ancestor of all Wolbachia and mitochondrial genomes in D. melanogaster dates to around 8,000 years ago. We find evidence for a recent incomplete global replacement of ancestral Wolbachia and mtDNA lineages, which is likely to be one of several similar incomplete replacement events that have occurred since the out-of-Africa migration that allowed D. melanogaster to colonize worldwide habitats.

Finding the sources of missing heritability in a yeast cross

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Finding the sources of missing heritability in a yeast cross

Joshua S. Bloom, Ian M. Ehrenreich, Wesley Loo, Thúy-Lan Võ Lite, Leonid Kruglyak
(Submitted on 14 Aug 2012)

For many traits, including susceptibility to common diseases in humans, causal loci uncovered by genetic mapping studies explain only a minority of the heritable contribution to trait variation. Multiple explanations for this “missing heritability” have been proposed. Here we use a large cross between two yeast strains to accurately estimate different sources of heritable variation for 46 quantitative traits and to detect underlying loci with high statistical power. We find that the detected loci explain nearly the entire additive contribution to heritable variation for the traits studied. We also show that the contribution to heritability of gene-gene interactions varies among traits, from near zero to 50%. Detected two-locus interactions explain only a minority of this contribution. These results substantially advance our understanding of the missing heritability problem and have important implications for future studies of complex and quantitative traits.