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Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (1 every 17 bases) and geographically localized, so that even with large sample(More)
Testing one SNP at a time does not fully realise the potential of genome-wide association studies to identify multiple causal variants, which is a plausible scenario for many complex diseases. We show that simultaneous analysis of the entire set of SNPs from a genome-wide study to identify the subset that best predicts disease outcome is now feasible,(More)
Simulation is an invaluable tool for investigating the effects of various population genetics modeling assumptions on resulting patterns of genetic diversity, and for assessing the performance of statistical techniques, for example those designed to detect and measure the genomic effects of selection. It is also used to investigate the effectiveness of(More)
We consider the analysis of multiple single nucleotide polymorphisms (SNPs) within a gene or region. The simplest analysis of such data is based on a series of single SNP hypothesis tests, followed by correction for multiple testing, but it is intuitively plausible that a joint analysis of the SNPs will have higher power, particularly when the causal locus(More)
Markov chain Monte Carlo techniques have revolutionized the field of Bayesian statistics. Their enormous power and their gener-alizability have rendered them the method of choice for statistical inference in many scientific disciplines. Their power is so great that they can even accommodate situations in which the structure of the statistical model itself(More)
BACKGROUND FREGENE simulates sequence-level data over large genomic regions in large populations. Because, unlike coalescent simulators, it works forwards through time, it allows complex scenarios of selection, demography, and recombination to be modelled simultaneously. Detailed tracking of sites under selection is implemented in FREGENE and provides the(More)
OBJECTIVE Studies of major depression in twins and families have shown moderate to high heritability, but extensive molecular studies have failed to identify susceptibility genes convincingly. To detect genetic variants contributing to major depression, the authors performed a genome-wide association study using 1,636 cases of depression ascertained in the(More)
OBJECTIVE The authors sought to determine whether prenatal exposure to infection and a positive family history of psychotic disorders interact synergistically to increase the risk of later developing schizophrenia. METHOD The authors linked two national registers, the Medical Birth Register and the Finnish Population Register, to identify all women in(More)
BACKGROUND Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. METHODS(More)
BACKGROUND Ischaemic stroke in persons of European descent has a genetic basis, but whether the stroke-susceptibility alleles, the strength of any association, and the extent of their attributable risks are the same in persons of non-European descent remains unanswered. Whether ethnicity itself has a relevant or substantial contribution on those effect(More)