Abstract:
:DNA methylation is an important epigenetic mechanism that has been linked to complex diseases and is of great interest to researchers as a potential link between genome, environment, and disease. As the scale of DNA methylation association studies approaches that of genome-wide association studies, issues such as population stratification will need to be addressed. It is well-documented that failure to adjust for population stratification can lead to false positives in genetic association studies, but population stratification is often unaccounted for in DNA methylation studies. Here, we propose several approaches to correct for population stratification using principal components (PCs) from different subsets of genome-wide methylation data. We first illustrate the potential for confounding due to population stratification by demonstrating widespread associations between DNA methylation and race in 388 individuals (365 African American and 23 Caucasian). We subsequently evaluate the performance of our PC-based approaches and other methods in adjusting for confounding due to population stratification. Our simulations show that (1) all of the methods considered are effective at removing inflation due to population stratification, and (2) maximum power can be obtained with single-nucleotide polymorphism (SNP)-based PCs, followed by methylation-based PCs, which outperform both surrogate variable analysis and genomic control. Among our different approaches to computing methylation-based PCs, we find that PCs based on CpG sites chosen for their potential to proxy nearby SNPs can provide a powerful and computationally efficient approach to adjust for population stratification in DNA methylation studies when genome-wide SNP data are unavailable.
journal_name
Genet Epidemioljournal_title
Genetic epidemiologyauthors
Barfield RT,Almli LM,Kilaru V,Smith AK,Mercer KB,Duncan R,Klengel T,Mehta D,Binder EB,Epstein MP,Ressler KJ,Conneely KNdoi
10.1002/gepi.21789subject
Has Abstractpub_date
2014-04-01 00:00:00pages
231-41issue
3eissn
0741-0395issn
1098-2272journal_volume
38pub_type
杂志文章abstract::The heritability of most complex traits is driven by variants throughout the genome. Consequently, polygenic risk scores, which combine information on multiple variants genome-wide, have demonstrated improved accuracy in genetic risk prediction. We present a new two-step approach to constructing genome-wide polygenic ...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.22245
更新日期:2019-10-01 00:00:00
abstract::The association between insulin-dependent diabetes mellitus (IDDM) and an allele of a restriction fragment length polymorphism (RFLP) 5' to the coding region of the insulin gene has raised the possibility that variation in the vicinity of the insulin gene confers susceptibility to IDDM. To test this hypothesis, the di...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.1370060113
更新日期:1989-01-01 00:00:00
abstract::Inaccurate genetic (or linkage) maps can reduce the power to detect linkage, increase type I error, and distort haplotype and relationship inference. To improve the accuracy of existing maps, I propose a meta-analysis-based method that combines independent map estimates into a single estimate of the linkage map. The m...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.20221
更新日期:2007-07-01 00:00:00
abstract::Complex traits have been modeled under various modes of two-locus inheritance. One example of a two-locus threshold model is the situation where an individual is susceptible to a disease trait if he or she carries three or more disease alleles. Under this model, if each locus is examined individually the inheritance a...
journal_title:Genetic epidemiology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1002/(SICI)1098-2272(1997)14:6<1097::AID-GEPI89
更新日期:1997-01-01 00:00:00
abstract::A robust approach for estimating standard errors of variance components by using quantitative phenotypes from families ascertained through a proband with an extreme phenotypic value is presented. Estimators that use the multivariate normal distribution as a "working likelihood" are obtained by computing conditional ln...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.1370040305
更新日期:1987-01-01 00:00:00
abstract::Variable selection is growing in importance with the advent of high throughput genotyping methods requiring analysis of hundreds to thousands of single nucleotide polymorphisms (SNPs) and the increased interest in using these genetic studies to better understand common, complex diseases. Up to now, the standard approa...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.20353
更新日期:2009-01-01 00:00:00
abstract::Several approaches were taken to identify the loci contributing to the quantitative and qualitative phenotypes in the Genetic Analysis Workshop 12 simulated data set. To identify possible quantitative trait loci (QTL), the quantitative traits were analyzed using SOLAR. The four replicates identified as the "best repli...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.2001.21.s1.s732
更新日期:2001-01-01 00:00:00
abstract::Association mapping for complex diseases using unrelated individuals can be more powerful than family-based analysis in many settings. In addition, this approach has major practical advantages, including greater efficiency in sample recruitment. Association mapping may lead to false-positive findings, however, if popu...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.210
更新日期:2002-08-01 00:00:00
abstract::The restricted partition method (RPM) is a partitioning algorithm for examining multi-locus genotypes as (potentially non-additive) predictors of a quantitative trait. The motivating application was to develop a robust method to examine quantitative phenotypes for epistasis (gene-gene interactions), but the method can...
journal_title:Genetic epidemiology
pub_type: 杂志文章,评审
doi:10.1002/gepi.20006
更新日期:2004-09-01 00:00:00
abstract::This paper describes a general genetic model which encompasses both autosomal and X-linked inheritance as submodels. It allows one to test for X-linked inheritance of a trait by comparing the likelihood of X-linked inheritance to the likelihood of the general genetic model. The general model is formulated as two loci,...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.1370010105
更新日期:1984-01-01 00:00:00
abstract::Noncoding DNA contains gene regulatory elements that alter gene expression, and the function of these elements can be modified by genetic variation. Massively parallel reporter assays (MPRA) enable high-throughput identification and characterization of functional genetic variants, but the statistical methods to identi...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.22337
更新日期:2020-10-01 00:00:00
abstract::In the past decade, many genome-wide association studies (GWASs) have been conducted to explore association of single nucleotide polymorphisms (SNPs) with complex diseases using a case-control design. These GWASs not only collect information on the disease status (primary phenotype, D) and the SNPs (genotypes, X), but...
journal_title:Genetic epidemiology
pub_type: 杂志文章,随机对照试验
doi:10.1002/gepi.22045
更新日期:2017-07-01 00:00:00
abstract::We propose a new approach to detect gene × gene joint action in genome-wide association studies (GWASs) for case-control designs. This approach offers an exhaustive search for all two-way joint action (including, as a special case, single gene action) that is computationally feasible at the genome-wide level and has r...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.21779
更新日期:2014-01-01 00:00:00
abstract::The study of the genetic component of early-onset diseases requires investigation into parental genetic effects, particularly those mediated by the mother who can influence the offspring's risk of disease through the effects of her genes acting directly on the intrauterine milieu or indirectly through maternal-gene ch...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.20602
更新日期:2011-09-01 00:00:00
abstract::Several statistical tests for linkage between a disease susceptibility locus and a marker locus for sib-pair data are examined analytically. Two common statistics, a test based on the mean number of marker alleles shared identical by descent by sib-pairs, and a test based on the proportion of sib-pairs sharing exactly...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.1370070506
更新日期:1990-01-01 00:00:00
abstract::Path analysis of nuclear family data has been widely applied to resolve genetic and environmental sources of familial resemblance. Here we report the results of a systematic evaluation of the effects of departures from five modeling assumptions often made when analyzing nuclear family data; i) the observed environment...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.1370060207
更新日期:1989-01-01 00:00:00
abstract::Bone mass may be so reduced in some individuals as to be characterized as osteoporotic, with resulting fracture, particularly of the proximal femur, vertebrae, or wrist. We identified 34 mother-daughter sets (n = 70) and 29 sibling sets (n = 59) from a community study of bone mass correlates to assess the degree of re...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.1370030204
更新日期:1986-01-01 00:00:00
abstract::We combined the five chromosome 18 bipolar affective disorder data sets provided by GAW10, totaling 185 families with 3,394 individuals, and performed analysis of differential parental transmission and chromosome 18 marker allele sharing in families with transmission through fathers vs those through mothers. Results i...
journal_title:Genetic epidemiology
pub_type: 临床试验,杂志文章
doi:10.1002/(SICI)1098-2272(1997)14:6<665::AID-GEPI19>
更新日期:1997-01-01 00:00:00
abstract::Alcohol dependence often is a familial disorder and has a genetic component. Research in causative factors of alcoholism is coordinated by a multi-center program, COGA [The Collaborative Study on the Genetics of Alcoholism, Begleiter et al., 1995]. We analyzed a subset of the COGA family sample, 84 pedigrees of Caucas...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.1370170768
更新日期:1999-01-01 00:00:00
abstract::Nontraditional glycemic biomarkers, including fructosamine, glycated albumin, and 1,5-anhydroglucitol (1,5-AG) are potential alternatives or complement to traditional measures of hyperglycemia. Genetic variants are associated with these biomarkers, but the heritability, or extent to which genetics control their variat...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.22243
更新日期:2019-10-01 00:00:00
abstract::We have conducted a simulation study in small pedigrees to investigate the power to detect linkage and heterogeneity for a disorder due to either one of two independent disease loci. We have considered a highly polymorphic marker locus (PIC = 70%) linked to one disease locus and unlinked to the second. The power to de...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.1370070306
更新日期:1990-01-01 00:00:00
abstract::We investigate the relevance of the genetic determination of bone mineral density (BMD) variation to that of differential risk to osteoporotic fractures (OF). The high heritability (h(2)) of BMD and the significant phenotypic correlations between high BMD and low risk to OF are well known. Little is reported on h(2) f...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.1040
更新日期:2002-01-01 00:00:00
abstract::A range of study designs, using unrelated or family controls, were used to investigate the pattern of association with disease of single nucleotide polymorphisms (SNPs) within candidate gene 1 (simulated data). Strong evidence of disease association at the functional locus was detected using all study designs, and in ...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.2001.21.s1.s415
更新日期:2001-01-01 00:00:00
abstract::A method is described for estimating excess relative risks of a disease from familial factors. Beginning with population-based series of cases and controls, a cohort of each subject's relatives is formed and checked for disease against a population based registry. The disease experience of the cohort formed from each ...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.1370120306
更新日期:1995-01-01 00:00:00
abstract::In diseases with a complex mode of inheritance, families with multiple affected individuals are difficult to ascertain. The haplotype sharing statistic (HSS) uses (hidden) co-ancestry between affected individuals from a founder population. These affected individuals will likely not only share the same mutation(s), but...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/(SICI)1098-2272(1997)14:6<915::AID-GEPI59>
更新日期:1997-01-01 00:00:00
abstract::It is believed that interactions among genes (epistasis) may play an important role in susceptibility to common diseases (Moore and Williams [2002]. Ann Med 34:88-95; Ritchie et al. [2001]. Am J Hum Genet 69:138-147). To study the underlying genetic variants of diseases, genome-wide association studies (GWAS) that sim...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.20514
更新日期:2010-09-01 00:00:00
abstract::The extended transmission disequilibrium test (ETDT) of Sham and Curtis [1995] is a powerful test of the null hypothesis of no linkage between a multi-allelic marker locus and a disease susceptibility locus of unknown location in the presence of association between alleles at the two loci. We propose a generalization ...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.13701707108
更新日期:1999-01-01 00:00:00
abstract::Penalized regression methods offer an attractive alternative to single marker testing in genetic association analysis. Penalized regression methods shrink down to zero the coefficient of markers that have little apparent effect on the trait of interest, resulting in a parsimonious subset of what we hope are true perti...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.20543
更新日期:2010-12-01 00:00:00
abstract::We investigated the utility of two approaches for exploiting pleiotropy to search for genes influencing related traits. To do this we first assessed the genetic correlations among a set of five closely related quantitative traits (Q1, Q2, Q3, Q4, Q5). We then used the genetic correlations among these five traits both ...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/(SICI)1098-2272(1997)14:6<975::AID-GEPI69>
更新日期:1997-01-01 00:00:00
abstract::We set out to apply conventional analytic methods to a GAW data set of nuclear families with an oligogenic disease that has a population prevalence of 0.023. We chose methods generally applied to disorders with at least one major gene. Our approaches included: 1) complex segregation analysis under two models of ascert...
journal_title:Genetic epidemiology
pub_type: 杂志文章
doi:10.1002/gepi.1370120613
更新日期:1995-01-01 00:00:00