Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
Subject terms: Genome-wide association studies
http://www.nature.com/nature/journal/v511/n7510/full/nature13595.html
Genomic inflation factors under polygenic inheritance
Abstract: Population structure, including population stratification and cryptic relatedness, can cause spurious associations in genome-wide association studies (GWAS). Usually, the scaled median or mean test statistic for association calculated from multiple single-nucleotide-polymorphisms across the genome is used to assess such effects, and ‘genomic control' can be applied subsequently to adjust test statistics at individual loci by a genomic inflation factor. Published GWAS have clearly shown that there are many loci underlying genetic variation for a wide range of complex diseases and traits, implying that a substantial proportion of the genome should show inflation of the test statistic. Here, we show by theory, simulation and analysis of data that in the absence of population structure and other technical artefacts, but in the presence of polygenic inheritance, substantial genomic inflation is expected. Its magnitude depends on sample size, heritability, linkage disequilibrium structure and the number of causal variants. Our predictions are consistent with empirical observations on height in independent samples of ~4000 and ~133 000 individuals.
Keywords: genome-wide association study, genomic inflation factor, polygenic inheritance
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137506/
In population genetics, linkage disequilibrium is the non-random association of alleles at two or more loci, that descend from single, ancestral chromosomes
linkage equilibrium D = 0, is when PA * PB = PAB (ie. A is found and B is found)
http://en.wikipedia.org/wiki/Linkage_disequilibrium
Linkage disequilibrium makes tightly linked
variants strongly correlated producing cost
savings for association studies
http://www.sph.umich.edu/csg/abecasis/class/666.03.pdf
Population stratification is the presence of a systematic difference in allele frequencies between subpopulations in a population possibly due to different ancestry, especially in the context of association studies.
The two most widely used approaches to this problem include genomic control, which is a relatively nonparametric method for controlling the inflation of test statistics,[2] and structured association methods,[3] which use genetic information to estimate and control for population structure.
Genomic Control works by using markers that are not linked with the trait in question to correct for any inflation of the statistic caused by population stratification
http://en.wikipedia.org/wiki/Population_stratification
The Hardy–Weinberg principle states that allele and genotype frequencies in a population will remain constant from generation to generation in the absence of other evolutionary influences.
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