Rare Variant Analysis for Family-Based Design

De, Gourab; Yip, Wai‐Ki; Ionita‐Laza, Iuliana; Laird, Nan M.

doi:10.1371/journal.pone.0048495

Cited by 81 publications

(103 citation statements)

References 30 publications

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“…Twenty-five nuclear families whose probands carried rare functional variants (a total of 65 affected and 17 unaffected subjects) were resequenced in the follow-up step. To perform "burden" analysis on 4 missense single nucleotide polymorphisms (SNPs) (rs75932628, rs143332484, rs2234253, and rs200392967) in exon 2 of TREM2 identified by our sequencing efforts, we based our statistical analysis on the rare variant extension of FBAT 26,27 (version 2.0.4 beta). Based on the MAF of the subset of unrelated probands (n 5 25) in our follow-up sample, SNPs with MAF ,0.08 (arbitrarily chosen) were considered as rare variants; rs75932628-T was the most common of the 4 SNPs with a MAF 5 0.19.…”

Section: Statistical Analyses a Family-based Association Test (Fbat)mentioning

confidence: 99%

The rare TREM2 R47H variant exerts only a modest effect on Alzheimer disease risk

et al. 2014

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Objectives: Recently, 2 independent studies reported that a rare missense variant, rs75932628 (R47H), in exon 2 of the gene encoding the "triggering receptor expressed on myeloid cells 2" (TREM2) significantly increases the risk of Alzheimer disease (AD) with an effect size comparable to that of the APOE e4 allele. Methods:In this study, we attempted to replicate the association between rs75932628 and AD risk by directly genotyping rs75932628 in 2 independent Caucasian family cohorts consisting of 927 families (with 1,777 affected and 1,235 unaffected) and in 2 Caucasian case-control cohorts composed of 1,314 cases and 1,609 controls. In addition, we imputed genotypes in 3 independent Caucasian case-control cohorts containing 1,906 cases and 1,503 controls.Results: Meta-analysis of the 2 family-based and the 5 case-control cohorts yielded a p value of 0.0029, while the overall summary estimate (using case-control data only) resulted in an odds ratio of 1.67 (95% confidence interval 0.95-2.92) for the association between the TREM2 R47H and increased AD risk.Conclusions: While our results serve to confirm the association between R47H and risk of AD, the observed effect on risk was substantially smaller than that previously reported. Neurology ®

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Section: Statistical Analyses a Family-based Association Test (Fbat)mentioning

confidence: 99%

The rare TREM2 R47H variant exerts only a modest effect on Alzheimer disease risk

et al. 2014

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“…Zhu and Xiong [40] transformed a population-based test to the familybased test by calculating the covariance matrix of the functional principal-component scores, and developed the family-based functional principal-component analysis (FPCA) for qualitative traits. De et al [22] proposed a method (FBAT-T) in a family-based design by extending the traditional single-SNP Family-Based Association Test (FBAT). Sha et al [26] proposed a test for Testing the Optimally Weighted combination of variants based on data of Parents and Affected Children (TOW-PAC).…”

Section: Category 3: Methods For Family-based Designsmentioning

confidence: 99%

“…In addition, population-based tests can be seriously confounded by population stratification in rare variant association studies while family-based tests are robust to population stratification. So far, only a few family-based rare variant association methods have been developed, including the sib-pair and odds ratio weighted sum statistics (SPWSS, ORWSS) [20], two adaptive weighting methods (AW-FBAT, AW-Joint) [21], the FBAT-based test (FBAT-T) [22], the TOW for a family-based design (TOW-F) [23], and the TOW for sib-pair designs (TOW-sib) [24], among others. In this article, we will provide a general review of the literature for rare variant association studies.…”

Section: Introductionmentioning

confidence: 99%

Literature Reviews on Methods for Rare Variant Association Studies

Shurong

Shuanglin²,

Qiuying³

2016

Human Genet Embryol

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The widespread availability of genome sequencing data has yielded different rare variant association methods in population-based or family-based designs. However, it is challenging to know which method is appropriate in practice. Our purpose of this paper is to provide a general review of the literature for rare variant association studies and suggestions on future research directions. This paper discusses methods for recent rare variant association studies in three categories. The first two categories are for population-based designs, with/without considering the direction of the effects of causal rare variants. In the third category, methods for family-based designs are concluded.

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“…FB-Burden uses the weighted-sum approach, which is similar to the FBAT test for rare variants [11]. FB-SKAT extends the SKAT approach to family data.…”

Section: Methodsmentioning

confidence: 99%

Family-Based Association Test Using Both Common and Rare Variants and Accounting for Directions of Effects for Sequencing Data

2014

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Current family-based association tests for sequencing data were mainly developed for identifying rare variants associated with a complex disease. As the disease can be influenced by the joint effects of common and rare variants, common variants with modest effects may not be identified by the methods focusing on rare variants. Moreover, variants can have risk, neutral, or protective effects. Association tests that can effectively select groups of common and rare variants that are likely to be causal and consider the directions of effects have become important. We developed the Ordered Subset - Variable Threshold - Pedigree Disequilibrium Test (OVPDT), a combination of three algorithms, for association analysis in family sequencing data. The ordered subset algorithm is used to select a subset of common variants based on their relative risks, calculated using only parental mating types. The variable threshold algorithm is used to search for an optimal allele frequency threshold such that rare variants below the threshold are more likely to be causal. The PDT statistics from both rare and common variants selected by the two algorithms are combined as the OVPDT statistic. A permutation procedure is used in OVPDT to calculate the p-value. We used simulations to demonstrate that OVPDT has the correct type I error rates under different scenarios and compared the power of OVPDT with two other family-based association tests. The results suggested that OVPDT can have more power than the other tests if both common and rare variants have effects on the disease in a region.

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Rare Variant Analysis for Family-Based Design

Cited by 81 publications

References 30 publications

The rare TREM2 R47H variant exerts only a modest effect on Alzheimer disease risk

The rare TREM2 R47H variant exerts only a modest effect on Alzheimer disease risk

Literature Reviews on Methods for Rare Variant Association Studies

Family-Based Association Test Using Both Common and Rare Variants and Accounting for Directions of Effects for Sequencing Data

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