2,522 research outputs found
The admixture maximum likelihood test to test for association between rare variants and disease phenotypes.
BACKGROUND: The development of genotyping arrays containing hundreds of thousands of rare variants across the genome and advances in high-throughput sequencing technologies have made feasible empirical genetic association studies to search for rare disease susceptibility alleles. As single variant testing is underpowered to detect associations, the development of statistical methods to combine analysis across variants - so-called "burden tests" - is an area of active research interest. We previously developed a method, the admixture maximum likelihood test, to test multiple, common variants for association with a trait of interest. We have extended this method, called the rare admixture maximum likelihood test (RAML), for the analysis of rare variants. In this paper we compare the performance of RAML with six other burden tests designed to test for association of rare variants. RESULTS: We used simulation testing over a range of scenarios to test the power of RAML compared to the other rare variant association testing methods. These scenarios modelled differences in effect variability, the average direction of effect and the proportion of associated variants. We evaluated the power for all the different scenarios. RAML tended to have the greatest power for most scenarios where the proportion of associated variants was small, whereas SKAT-O performed a little better for the scenarios with a higher proportion of associated variants. CONCLUSIONS: The RAML method makes no assumptions about the proportion of variants that are associated with the phenotype of interest or the magnitude and direction of their effect. The method is flexible and can be applied to both dichotomous and quantitative traits and allows for the inclusion of covariates in the underlying regression model. The RAML method performed well compared to the other methods over a wide range of scenarios. Generally power was moderate in most of the scenarios, underlying the need for large sample sizes in any form of association testing.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are
Candidate Sequence Variants for Polyautoimmunity and Multiple Autoimmune Syndrome from a Colombian Genetic Isolate: Implications for Population Genetics
Autoimmunity is an immunological disorder whereby patients have
lost immunological tolerance to self-antigen. It has extreme
financial and socioeconomic burden with costs of over 100 billion
dollars in the USA alone, and an estimated prevalence of 9.4%,
and evidence indicates that this estimate has increased at a rate
of 5% per year for the past 3 years. These phenotypes can be
manifested in more severe forms through polyautoimmunity, whereby
patients are carrying 2 or more autoimmune conditions. In
addition to that, there is also the most extreme phenotype of
autoimmunity known as the Multiple Autoimmune Syndrome (MAS),
consisting of cases where patients have 3 or more autoimmune
diseases. These extreme phenotypes are extremely important for
genetic research as will be elaborated upon in this thesis. For
more than 20 years, pedigrees from the world’s largest known
genetic isolate, from the Paisa region of Colombia have been
ascertained and thoroughly followed by Dr. Juan-Manuel Anaya and
Dr. Mauricio Arcos-Burgos. This population has maintained its
status as a genetic isolate since the 16th century, during the
early colonization by the Spanish Conquistadors.
In this thesis, our attempts in identifying potential candidate
variants potentially underpinning the genetic etiology of
autoimmune conditions in this population is facilitated by the
fact that families are derived from individuals carrying extreme
phenotypes, from familial cohorts where genetic homogeneity is
maximized. Candidates are identified in both sporadic as well as
familial cases. This is primarily achieved through combination of
linkage analysis and association tests for both rare and common
variants, derived from variant-calling pipelines and that had
undergone quality control, filtering and functional annotation,
via bioinformatic anlayses. Genes harbouring variants with
significant evidence of linkage and association were primarily
involved in negative regulation of apoptosis, phagocytosis,
regulation of endopeptidase activity, response to
lipopolysaccharides and plasminogen urokinase receptor activity.
These findings, that were obtained by utilizing the combinations
of statistical as well as network-based analyses have relevant
potential implications in autoimmunity, and can be further
supported with additional studies
Enhanced Statistical Tests for GWAS in Admixed Populations: Assessment using African Americans from CARe and a Breast Cancer Consortium
While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations
Population Structure and Cryptic Relatedness in Genetic Association Studies
We review the problem of confounding in genetic association studies, which
arises principally because of population structure and cryptic relatedness.
Many treatments of the problem consider only a simple ``island'' model of
population structure. We take a broader approach, which views population
structure and cryptic relatedness as different aspects of a single confounder:
the unobserved pedigree defining the (often distant) relationships among the
study subjects. Kinship is therefore a central concept, and we review methods
of defining and estimating kinship coefficients, both pedigree-based and
marker-based. In this unified framework we review solutions to the problem of
population structure, including family-based study designs, genomic control,
structured association, regression control, principal components adjustment and
linear mixed models. The last solution makes the most explicit use of the
kinships among the study subjects, and has an established role in the analysis
of animal and plant breeding studies. Recent computational developments mean
that analyses of human genetic association data are beginning to benefit from
its powerful tests for association, which protect against population structure
and cryptic kinship, as well as intermediate levels of confounding by the
pedigree.Comment: Published in at http://dx.doi.org/10.1214/09-STS307 the Statistical
Science (http://www.imstat.org/sts/) by the Institute of Mathematical
Statistics (http://www.imstat.org
Estimating relationships between phenotypes and subjects drawn from admixed families.
Background: Estimating relationships among subjects in a sample, within family structures or caused by population substructure, is complicated in admixed populations. Inaccurate allele frequencies can bias both kinship estimates and tests for association between subjects and a phenotype. We analyzed the simulated and real family data from Genetic Analysis Workshop 19, and were aware of the simulation model.
Results: We found that kinship estimation is more accurate when marker data include common variants whose frequencies are less variable across populations. Estimates of heritability and association vary with age for longitudinally measured traits. Accounting for local ancestry identified different true associations than those identified by a traditional approach. Principal components aid kinship estimation and tests for association, but their utility is influenced by the frequency of the markers used to generate them.
Conclusions: Admixed families can provide a powerful resource for detecting disease loci, as well as analytical challenges. Allele frequencies, although difficult to adequately estimate in admixed populations, have a strong impact on the estimation of kinship, ancestry, and association with phenotypes. Approaches that acknowledge population structure in admixed families outperform those which ignore it
Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates.
Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 838 individuals and high-coverage whole-genome sequencing of 449 individuals. We compared polygenic risk scores (PRS), estimated using the latest BP1 genome-wide association study (GWAS) summary statistics, between BP1 individuals and related controls. We also evaluated whether BP1 individuals had a higher burden of rare deleterious single-nucleotide variants (SNVs) and rare copy number variants (CNVs) in a set of genes related to BP1. We found that compared with unaffected relatives, BP1 individuals had higher PRS estimated from BP1 GWAS statistics (P = 0.001 ~ 0.007) and displayed modest increase in burdens of rare deleterious SNVs (P = 0.047) and rare CNVs (P = 0.002 ~ 0.033) in genes related to BP1. We did not observe rare variants segregating in the pedigrees. These results suggest that small-to-moderate effect rare and common variants are more likely to contribute to BP1 risk in these extended pedigrees than a few large-effect rare variants
Summaries of plenary, symposia, and oral sessions at the XXII World Congress of Psychiatric Genetics, Copenhagen, Denmark, 12-16 October 2014
The XXII World Congress of Psychiatric Genetics, sponsored by the International Society of Psychiatric Genetics, took place in Copenhagen, Denmark, on 12-16 October 2014. A total of 883 participants gathered to discuss the latest findings in the field. The following report was written by student and postdoctoral attendees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported
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