Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

On the Classification of Epistatic Interactions

Modern genomewide association studies are characterized by the problem of “missing heritability.” Epistasis, or genetic interaction, has been suggested as a possible explanation for the relatively small contribution of single significant associations to the fraction of variance explained. Of particular concern to investigators of genetic interactions is how to best represent and define epistasis. Previous studies have found that the use of different quantitative definitions for genetic interaction can lead to different conclusions when constructing genetic interaction networks and when addressing evolutionary questions. We suggest that instead, multiple representations of epistasis, or epistatic “subtypes,” may be valid within a given system. Selecting among these epistatic subtypes may provide additional insight into the biological and functional relationships among pairs of genes. In this study, we propose maximum-likelihood and model selection methods in a hypothesis-testing framework to choose epistatic subtypes that best represent functional relationships for pairs of genes on the basis of fitness data from both single and double mutants in haploid systems. We gauge the performance of our method with extensive simulations under various interaction scenarios. Our approach performs reasonably well in detecting the most likely epistatic subtype for pairs of genes, as well as in reducing bias when estimating the epistatic parameter (ɛ). We apply our approach to two available data sets from yeast (Saccharomyces cerevisiae) and demonstrate through overlap of our identified epistatic pairs with experimentally verified interactions and functional links that our results are likely of biological significance in understanding interaction mechanisms. We anticipate that our method will improve detection of epistatic interactions and will help to unravel the mysteries of complex biological systems

The Role of Selection in Shaping Diversity of Natural M. tuberculosis Populations

Mycobacterium tuberculosis ( M.tb ), the cause of tuberculosis (TB), is estimated to infect a new host every second. While analyses of genetic data from natural populations of M.tb have emphasized the role of genetic drift in shaping patterns of diversity, the influence of natural selection on this successful pathogen is less well understood. We investigated the effects of natural selection on patterns of diversity in 63 globally extant genomes of M.tb and related pathogenic mycobacteria. We found evidence of strong purifying selection, with an estimated genome-wide selection coefficient equal to −9.5×10 −4 (95% CI −1.1×10 −3 to −6.8×10 −4 ); this is several orders of magnitude higher than recent estimates for eukaryotic and prokaryotic organisms. We also identified different patterns of variation across categories of gene function. Genes involved in transport and metabolism of inorganic ions exhibited very low levels of non-synonymous polymorphism, equivalent to categories under strong purifying selection (essential and translation-associated genes). The highest levels of non-synonymous variation were seen in a group of transporter genes, likely due to either diversifying selection or local selective sweeps. In addition to selection, we identified other important influences on M.tb genetic diversity, such as a 25-fold expansion of global M.tb populations coincident with explosive growth in human populations (estimated timing 1684 C.E., 95% CI 1620–1713 C.E.). These results emphasize the parallel demographic histories of this obligate pathogen and its human host, and suggest that the dominant effect of selection on M.tb is removal of novel variants, with exceptions in an interesting group of genes involved in transportation and defense. We speculate that the hostile environment within a host imposes strict demands on M.tb physiology, and thus a substantial fitness cost for most new mutations. In this respect, obligate bacterial pathogens may differ from other host-associated microbes such as symbionts. Mycobacterium tuberculosis ( M.tb ), the etiologic agent of tuberculosis (TB), is a highly prevalent pathogen of humans, estimated to infect one-third of the world's population. Previous investigations of M.tb evolution have emphasized the influence of chance events on populations of these bacteria. To understand why this organism is so well adapted to its niche, we sought to characterize the influence of natural selection on M.tb . DNA sequence data from M.tb populations appeared to be strongly influenced by genome-wide selection against deleterious mutations. This type of selection was particularly evident in three functional categories: genes essential for infection (identified in an animal model of TB), genes involved in protein translation, and genes involved in trafficking and metabolism of inorganic ions. By contrast, a fourth category (‘defense’ genes) exhibited high levels of diversity, consistent with selection for advantageous mutations. In addition to effects of selection on M.tb genomic data, we identified the influence of a pronounced recent expansion in M.tb populations, coincident with explosive growth of human populations around the world. Our results suggest that growth of M.tb populations parallels that of its human host population, and that complex influences lead to emergence and maintenance of adaptive traits in M.tb

Linkage Disequilibrium and Demographic History of Wild and Domestic Canids

Assessing the extent of linkage disequilibrium (LD) in natural populations of a nonmodel species has been difficult due to the lack of available genomic markers. However, with advances in genotyping and genome sequencing, genomic characterization of natural populations has become feasible. Using sequence data and SNP genotypes, we measured LD and modeled the demographic history of wild canid populations and domestic dog breeds. In 11 gray wolf populations and one coyote population, we find that the extent of LD as measured by the distance at which r2 = 0.2 extends <10 kb in outbred populations to >1.7 Mb in populations that have experienced significant founder events and bottlenecks. This large range in the extent of LD parallels that observed in 18 dog breeds where the r2 value varies from ∼20 kb to >5 Mb. Furthermore, in modeling demographic history under a composite-likelihood framework, we find that two of five wild canid populations exhibit evidence of a historical population contraction. Five domestic dog breeds display evidence for a minor population contraction during domestication and a more severe contraction during breed formation. Only a 5% reduction in nucleotide diversity was observed as a result of domestication, whereas the loss of nucleotide diversity with breed formation averaged 35%

A Prospective Analysis of Genetic Variants Associated with Human Lifespan

We present a massive investigation into the genetic basis of human lifespan. Beginning with a genome-wide association (GWA) study using a de-identified snapshot of the unique AncestryDNA database – more than 300,000 genotyped individuals linked to pedigrees of over 400,000,000 people – we mapped six genome-wide significant loci associated with parental lifespan. We compared these results to a GWA analysis of the traditional lifespan proxy trait, age, and found only one locus, APOE, to be associated with both age and lifespan. By combining the AncestryDNA results with those of an independent UK Biobank dataset, we conducted a meta-analysis of more than 650,000 individuals and identified fifteen parental lifespan-associated loci. Beyond just those significant loci, our genome-wide set of polymorphisms accounts for up to 8% of the variance in human lifespan; this value represents a large fraction of the heritability estimated from phenotypic correlations between relatives

Simulation and inference under purifying selection and complete linkage.

<p>Results of four sets of simulation experiments (10,000 simulations/set). In all cases, a single completely linked locus of length equal to 2,753,618 bp was simulated under purifying selection, and inference of selection was done with a two parameter model (category of neutral sites plus single selection coefficient at remaining sites). The composite parameter γ ( = 2<i>N_es</i>) and proportion of neutral sites (<i>p₀</i>) were estimated from the simulated data. These are shown on the Y and X axes of each panel, respectively. The number of counts of simulations with estimates within each grid value is indicated in the color key. A) Simulated γ = 1, <i>p₀</i> = 0; B) Simulated γ = 10, <i>p₀</i> = 0; C) Simulated γ = 1, <i>p₀</i> = 0.9; D) Simulated γ = 10, <i>p₀</i> = 0.9. Simulations of relatively weak purifying selection (panels A & C) paradoxically result in inference of extremely strong purifying selection (γ∼−3,000) in a large proportion of cases. This pattern disappears when stronger selection is simulated (panel B). Even when 90% of sites are evolving neutrally, purifying selection is inferred at a large proportion of sites (panels C & D), likely due to linkage of sites.</p

Results of the McDonald-Kreitman test on whole genome sequences of <i>M.tb</i> and related mycobacteria.

a<p>d_N = fixed non-synonymous difference, d_S = fixed synonymous difference.</p>b<p>d_N = non-synonymous polymorphism, d_S = synonymous polymorphism.</p>c<p>chi-square test.</p

Observed folded site frequency spectrum (SFS) of synonymous and non-synonymous SNPs.

<p>Numbers of single nucleotide polymorphisms (SNPs, Y axis) in frequency classes 1–23 (X axis). The SFS is leptokurtic and bumpy, consistent with purifying selection and linkage of sites (see text).</p

Null distributions of median d_N/d_S for two COG categories.

<p>Distributions of median d_N/d_S from 10,000 simulations in which synonymous and non-synonymous sites within the COG category were shuffled randomly. Red lines show observed median d_N/d_S value for the category. <b>A</b>: category J, translation and ribosomal structure. <b>B</b>: category V, defense.</p