Dataset Information

The Rare-Variant Generalized Disequilibrium Test for Association Analysis of Nuclear and Extended Pedigrees with Application to Alzheimer Disease WGS Data.

ABSTRACT: Whole-genome and exome sequence data can be cost-effectively generated for the detection of rare-variant (RV) associations in families. Causal variants that aggregate in families usually have larger effect sizes than those found in sporadic cases, so family-based designs can be a more powerful approach than population-based designs. Moreover, some family-based designs are robust to confounding due to population admixture or substructure. We developed a RV extension of the generalized disequilibrium test (GDT) to analyze sequence data obtained from nuclear and extended families. The GDT utilizes genotype differences of all discordant relative pairs to assess associations within a family, and the RV extension combines the single-variant GDT statistic over a genomic region of interest. The RV-GDT has increased power by efficiently incorporating information beyond first-degree relatives and allows for the inclusion of covariates. Using simulated genetic data, we demonstrated that the RV-GDT method has well-controlled type I error rates, even when applied to admixed populations and populations with substructure. It is more powerful than existing family-based RV association methods, particularly for the analysis of extended pedigrees and pedigrees with missing data. We analyzed whole-genome sequence data from families affected by Alzheimer disease to illustrate the application of the RV-GDT. Given the capability of the RV-GDT to adequately control for population admixture or substructure and analyze pedigrees with missing genotype data and its superior power over other family-based methods, it is an effective tool for elucidating the involvement of RVs in the etiology of complex traits.

SUBMITTER: He Z

PROVIDER: S-EPMC5294711 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The Rare-Variant Generalized Disequilibrium Test for Association Analysis of Nuclear and Extended Pedigrees with Application to Alzheimer Disease WGS Data.

He Zongxiao Z Zhang Di D Renton Alan E AE Li Biao B Zhao Linhai L Wang Gao T GT Goate Alison M AM Mayeux Richard R Leal Suzanne M SM

American journal of human genetics 20170105 2

Whole-genome and exome sequence data can be cost-effectively generated for the detection of rare-variant (RV) associations in families. Causal variants that aggregate in families usually have larger effect sizes than those found in sporadic cases, so family-based designs can be a more powerful approach than population-based designs. Moreover, some family-based designs are robust to confounding due to population admixture or substructure. We developed a RV extension of the generalized disequilibr ...[more]

PMID: 28065470

Similar Datasets

Project description:BackgroundFor dichotomous traits, the generalized disequilibrium test with the moment estimate of the variance (GDT-ME) is a powerful family-based association method. Genomic imprinting is an important epigenetic phenomenon and currently, there has been increasing interest of incorporating imprinting to improve the test power of association analysis. However, GDT-ME does not take imprinting effects into account, and it has not been investigated whether it can be used for association analysis when the effects indeed exist.ResultsIn this article, based on a novel decomposition of the genotype score according to the paternal or maternal source of the allele, we propose the generalized disequilibrium test with imprinting (GDTI) for complete pedigrees without any missing genotypes. Then, we extend GDTI and GDT-ME to accommodate incomplete pedigrees with some pedigrees having missing genotypes, by using a Monte Carlo (MC) sampling and estimation scheme to infer missing genotypes given available genotypes in each pedigree, denoted by MCGDTI and MCGDT-ME, respectively. The proposed GDTI and MCGDTI methods evaluate the differences of the paternal as well as maternal allele scores for all discordant relative pairs in a pedigree, including beyond first-degree relative pairs. Advantages of the proposed GDTI and MCGDTI test statistics over existing methods are demonstrated by simulation studies under various simulation settings and by application to the rheumatoid arthritis dataset. Simulation results show that the proposed tests control the size well under the null hypothesis of no association, and outperform the existing methods under various imprinting effect models. The existing GDT-ME and the proposed MCGDT-ME can be used to test for association even when imprinting effects exist. For the application to the rheumatoid arthritis data, compared to the existing methods, MCGDTI identifies more loci statistically significantly associated with the disease.ConclusionsUnder complete and incomplete imprinting effect models, our proposed GDTI and MCGDTI methods, by considering the information on imprinting effects and all discordant relative pairs within each pedigree, outperform all the existing test statistics and MCGDTI can recapture much of the missing information. Therefore, MCGDTI is recommended in practice.

Project description:The Lundehund is an old dog breed with remarkable anatomical features including polydactyly in all four limbs and extraordinary flexibility of the spine. We genotyped 28 Lundehund using the canine Illumina high density beadchip to estimate the effective population size (Ne) and inbreeding coefficients as well as to identify potential regions of positive selection. The decay of linkage disequilibrium was slow with r2=0.95 in 50 kb distance. The last 7-200 generations ago, Ne was at 10-13. An increase of Ne was noted in the very recent generations with a peak value of 19 for Ne at generation 4. The FROH estimated for 50-, 65- and 358-SNP windows were 0.87, 087 and 0.81, respectively. The most likely estimates for FROH after removing identical-by-state segments due to linkage disequilibria were at 0.80-0.81. The extreme loss of heterozygosity has been accumulated through continued inbreeding over 200 generations within a probably closed population with a small effective population size. The mean inbreeding coefficient based on pedigree data for the last 11 generations (FPed=0.10) was strongly biased downwards due to the unknown coancestry of the founders in this pedigree data. The long-range haplotype test identified regions with genes involved in processes of immunity, olfaction, woundhealing and neuronal development as potential targets of selection. The genes QSOX2, BMPR1B and PRRX2 as well as MYOM1 are candidates for selection on the Lundehund characteristics small body size, increased number of digits per paw and extraordinary mobility, respectively. The objectives of the present study were to genotype 28 Lundehund using the canine Illumina high density beadchip (Illumina, San Diego, CA, USA) to estimate the effective population size (Ne) from data on linkage disequilibria (LD). We identified runs of homozygosity (ROH) as regions with a local loss of genetic variation. Inbreeding coefficients were calculated on the basis of pedigree data (FPed) and genotype information (FROH, FIS) to compare the results of these different methods for this population. We applied the long-range haplotype test to search for potential selective sweeps.

Dataset Information

The Rare-Variant Generalized Disequilibrium Test for Association Analysis of Nuclear and Extended Pedigrees with Application to Alzheimer Disease WGS Data.

Publications

The Rare-Variant Generalized Disequilibrium Test for Association Analysis of Nuclear and Extended Pedigrees with Application to Alzheimer Disease WGS Data.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets