Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types, bioRxiv, 2017-01-26

ABSTRACTGenetics can provide a systematic approach to discovering the tissues and cell types relevant for a complex disease or trait. Identifying these tissues and cell types is critical for following up on non-coding allelic function, developing ex-vivo models, and identifying therapeutic targets. Here, we analyze gene expression data from several sources, including the GTEx and PsychENCODE consortia, together with genome-wide association study (GWAS) summary statistics for 48 diseases and traits with an average sample size of 169,331, to identify disease-relevant tissues and cell types. We develop and apply an approach that uses stratified LD score regression to test whether disease heritability is enriched in regions surrounding genes with the highest specific expression in a given tissue. We detect tissue-specific enrichments at FDR < 5% for 34 diseases and traits across a broad range of tissues that recapitulate known biology. In our analysis of traits with observed central nervous system enrichment, we detect an enrichment of neurons over other brain cell types for several brain-related traits, enrichment of inhibitory over excitatory neurons for bipolar disorder but excitatory over inhibitory neurons for schizophrenia and body mass index, and enrichments in the cortex for schizophrenia and in the striatum for migraine. In our analysis of traits with observed immunological enrichment, we identify enrichments of T cells for asthma and eczema, B cells for primary biliary cirrhosis, and myeloid cells for Alzheimer's disease, which we validated with independent chromatin data. Our results demonstrate that our polygenic approach is a powerful way to leverage gene expression data for interpreting GWAS signal.

biorxiv genetics 0-100-users 2017

Modern human origins multiregional evolution of autosomes and East Asia origin of Y and mtDNA, bioRxiv, 2017-01-19

AbstractThe neutral theory has been used as a null model for interpreting nature and produced the Recent Out of Africa model of anatomically modern humans. Recent studies, however, have established that genetic diversities are mostly at maximum saturation levels maintained by selection, therefore challenging the explanatory power of the neutral theory and rendering the present molecular model of human origins untenable. Using improved methods and public data, we have revisited human evolution and found sharing of genetic variations among racial groups to be largely a result of parallel mutations rather than recent common ancestry and admixture as commonly assumed. We derived an age of 1.86-1.92 million years for the first split in modern human populations based on autosomal diversity data. We found evidence of modern Y and mtDNA originating in East Asia and dispersing via hybridization with archaic humans. Analyses of autosomes, Y and mtDNA all suggest that Denisovan and Neanderthal were archaic Africans with Eurasian admixtures and ancestors of South Asia Negritos and Aboriginal Australians. Verifying our model, we found more ancestry of Southern Chinese from Hunan in Africans relative to other East Asian groups examined. These results suggest multiregional evolution of autosomes and replacements of archaic Y and mtDNA by modern ones originating in East Asia, thereby leading to a coherent account of modern human origins.

biorxiv evolutionary-biology 0-100-users 2017

 

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