Family-Based Association Studies for Next-Generation Sequencing

Zhu, Yun; Xiong, Momiao

doi:10.1016/j.ajhg.2012.04.022

Cited by 49 publications

(87 citation statements)

References 34 publications

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“…We also compare our proposed method with one of the existing methods that are applicable to the affected sib-pair design. Although several methods 28,29 developed recently are applicable to the affected sib-pair design, we only choose SPWSS 28 to compare with because SPWSS is most relevant to our proposed method.…”

Section: Discussionmentioning

confidence: 99%

“…However, statistical methods for detecting rare variant associations under family-based designs have not received as much attention as methods for unrelated individuals, although family-based designs have been shown to improve power to detect rare variants. 28,29 Motivated by the facts that rare disease variants will be enriched in family data 33 and a large number of affected sib-pairs for a variety of diseases has been collected by traditional linkage studies, SPWSS is based on 1000 unrelated controls, 600 unrelated cases, and 200 affected sib-pairs. TOW-sib is based on 1000 unrelated controls and 500 affected sib-pairs.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…25 Therefore, family-based designs may have an important role in rare variant association studies. More recently, a couple of family-based rare variant association methods for quantitative traits 26,27 and for qualitative traits 28,29 have been developed.In this article, based on affected sib-pair data, we propose a test for Testing the effects of the Optimally Weighted combination of variants (TOW-sib). TOW-sib is based on the score test for testing the optimally weighted combination of variants derived from the retrospective likelihood of affected sib-pairs, unrelated controls, and possible unrelated cases.…”

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Test of rare variant association based on affected sib-pairs

Sha

Zhang

2014

Eur J Hum Genet

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With the development of sequencing techniques, there is increasing interest to detect associations between rare variants and complex traits. Quite a few statistical methods to detect associations between rare variants and complex traits have been developed for unrelated individuals. Statistical methods for detecting rare variant associations under family-based designs have not received as much attention as methods for unrelated individuals. Recent studies show that rare disease variants will be enriched in family data and thus family-based designs may improve power to detect rare variant associations. In this article, we propose a novel test to test association between the optimally weighted combination of variants and trait of interests for affected sib-pairs. The optimal weights are analytically derived and can be calculated from sampled genotypes and phenotypes. Based on the optimal weights, the proposed method is robust to the directions of the effects of causal variants and is less affected by neutral variants than existing methods are. Our simulation results show that, in all the cases, the proposed method is substantially more powerful than existing methods based on unrelated individuals and existing methods based on affected sib-pairs. INTRODUCTIONRecent studies show that the large number of disease-associated variants identified through genome-wide association studies account for only a small portion of the presumed phenotypic variation. 1 One of the potential sources of missing heritability is the contribution of rare variants. [2][3][4][5][6][7] The recent advances of sequencing technology have made directly testing rare variants possible. 8,9 Therefore, there is increasing interest to detect associations between rare variants and complex traits.Recently, several statistical methods to detect associations between rare variants and complex traits have been developed for unrelated individuals. These methods can be roughly divided into three groups: burden tests, quadratic tests, and combined tests. Burden tests include the cohort allelic sums test, 10 the combined multivariate and collapsing method, 11 the weighted sum statistic (WSS), 12 the variable minor allele frequency (MAF) threshold method, 13 and the cumulative minor-allele test 14 among others. Burden tests implicitly assume that all the rare variants are causal and the directions of the effects are all the same. If these assumptions are true, burden tests can be powerful tests; otherwise, burden tests can perform poorly. [15][16][17][18] Quadratic tests include C-alpha test, 19 sequence kernel association test, 15 and the test for Testing the effects of the Optimally Weighted combination of variants (TOW). 17 Quadratic tests also include adaptive weighting methods 20-24 since, as pointed out by Derkach et al, 18 adaptive weighting methods are operationally similar to quadratic tests. Quadratic tests are robust to the directions of the effects of causal variants and are less affected by neutral variants than burden tests are. If most of the ra...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Test of rare variant association based on affected sib-pairs

Sha

Zhang

2014

Eur J Hum Genet

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“…If one parent carries a copy of a rare allele, half of the offspring are expected to carry it, thus, variants that are rare in the general population could be common in certain families [39]. Therefore, family-based methods may improve power to detect causal rare variants [20,40]. Moreover, for rare variant associations, population-based association tests can be seriously confounded by population stratification while family-based association tests are robust to population stratification.…”

Section: Category 3: Methods For Family-based Designsmentioning

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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Identifying Rare Variants Associated with Complex Traits via Sequencing

Liu

Leal

2013

CP Human Genetics

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Although genome-wide association studies have been successful in detecting associations with common variants, there is currently an increasing interest in identifying low frequency and rare variants associated with complex traits. Next-generation sequencing technologies make it feasible to survey the full spectrum of genetic variation in coding regions or the entire genome. Due to the low frequency of rare variants, coupled with allelic heterogeneity, however, the association analysis for rare variants is challenging and traditional methods are ineffective. Recently a battery of new statistical methods has been proposed for identifying rare variants associated with complex traits. These methods test for associations by aggregating multiple rare variants across a gene or a genomic region, or a group of variants in the genome. In this Unit, we describe key concepts for rare variant association for complex traits, survey some of the recent methods and discuss their statistical power under various scenarios, and provide practical guidance on analyzing next-generation sequencing data for identifying rare variants associated with complex traits.

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Family-Based Association Studies for Next-Generation Sequencing

Cited by 49 publications

References 34 publications

Test of rare variant association based on affected sib-pairs

Test of rare variant association based on affected sib-pairs

Literature Reviews on Methods for Rare Variant Association Studies

Identifying Rare Variants Associated with Complex Traits via Sequencing

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