Weighted statistics for aggregation and linkage analysis of human longevity in selected families: The Leiden Longevity Study

Houwing-Duistermaat, Jeanine J.; Callegaro, Andrea; Beekman, Marian; Westendorp, Rudi G.J.; Slagboom, P. Eline; Houwelingen, Hans C. van

doi:10.1002/sim.3421

Cited by 13 publications

(17 citation statements)

References 36 publications

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“…Italy, UK, Denmark, France, Netherlands, Germany and Finland, a weighted NPL statistic was computed. The weights are the products of the age and sex specific cumulative hazard for the two siblings (Houwing-Duistermaat et al , 2009) that are based on country specific mortality rates. In this weighted NPL analysis extremely old sibling pairs obtain more weight (Fig.…”

Section: Resultsmentioning

confidence: 99%

Genome‐wide linkage analysis for human longevity: Genetics of Healthy Aging Study

et al. 2013

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Summary Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in fifteen study centers of eleven European countries as part of the Genetics of Healthy Ageing (GEHA) project. In the joint linkage analyses we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD=3.47), chromosome 17q12-q22 (LOD=2.95), chromosome 19p13.3-p13.11 (LOD=3.76) and chromosome 19q13.11-q13.32 (LOD=3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1,228 unrelated nonagenarian and 1,907 geographically matched controls. Using a fixed effect meta-analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (p-value=9.6 × 10−8). By combined modeling of linkage and association we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32 with p-value=0.02 and p-value=1.0 × 10−5, respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22 and 19p13.3-p13.11. Since the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.

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Section: Resultsmentioning

confidence: 99%

Genome‐wide linkage analysis for human longevity: Genetics of Healthy Aging Study

et al. 2013

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“…In the following sections we will compare the proposed score statistic (NPL ) with the unweighted mean test (NPL) [26] and with two score tests derived from additive gamma frailty models namely NPL 0 and NPL ( =1) . NPL 0 is a weighted NPL statistic where the excess IBD is weighted by the product of the martingale residuals of the two relatives (w = ( 1 − H 1 )( 2 − H 2 )) [10,18]. This statistic is derived from the retrospective likelihood corresponding to the model of Commenges [10].…”

Section: Score Test For Selected Sib Pairsmentioning

confidence: 99%

“…It is a weighted nonparametric linkage (NPL) statistic [16] where the (centered) proportions of alleles shared identical by descent (IBD) are weighted by a known function of the ages at onset of the two siblings. The proposed method is an extension of the score test proposed by Houwing-Duistermaat et al [18], which is derived from a shared frailty model. Both methods are similar in spirit to the linkage analysis of quantitative traits in selected samples [19][20][21][22], which also uses known information on the distribution of the phenotype.…”

Section: Introductionmentioning

confidence: 99%

Score test for age at onset genetic linkage analysis in selected sibling pairs

Callegaro

Houwelingen

Houwing-Duistermaat

2009

Statistics in Medicine

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A new score statistic is derived, which uses information from registries (age-specific incidences) and family studies (sib-sib marginal correlation) to weight affected sibling pairs according to their age at onset. Age at onset of sibling pairs is modelled by a gamma frailty model. From this model we derive a bivariate survival function, which depends on the marginal survival and on the marginal correlation. The score statistic for linkage is a classical nonparametric linkage (NPL) statistic where the identical by descent sharing is weighted by a particular function of the age at onset data. Since the statistic is based on survival models, it can also be applied to discordant and healthy sibling pairs. Simulation studies show that the proposed method is robust and more powerful than standard NPL methods. As illustration we apply the new score statistic to data from a breast cancer study.

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“…For association of X-linked SNPs and illustration of using imputed probabilities of the genotypes, we apply the proposed test to data from the Leiden Longevity Study (LLS) [ 17 , 41 ].…”

Section: Applications To Real Datamentioning

confidence: 99%

Genotype-Based Score Test for Association Testing in Families

Beekman

Meulenbelt

et al. 2015

Stat Biosci

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The multiplex-case and control design in which multiple cases are sampled from the same family is considered. In such studies phenotype information of the un-genotyped relatives might be available. We intend to use additional family information when performing genetic association tests. A score test is revisited to provide a flexible framework to accommodate various genetic models and to improve power of the association test by adding available family information. The proposed test accounts for correlations induced by multiple cases from the same pedigree, directly deals with X-linked SNPs in mixed-sex-related samples, and incorporates additional phenotypic information such as the number of (un-genotyped) siblings and parents with similar symptoms by assigning the weights to (genotyped) multiplex cases. In addition, the score test directly incorporates posterior probabilities of imputed genotypes, which leads to an efficiency measure that reflects imputation uncertainty on the test conducted. The proposed test is applied to real applications for illustration. Its efficiency is demonstrated via simulations.

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Weighted statistics for aggregation and linkage analysis of human longevity in selected families: The Leiden Longevity Study

Cited by 13 publications

References 36 publications

Genome‐wide linkage analysis for human longevity: Genetics of Healthy Aging Study

Genome‐wide linkage analysis for human longevity: Genetics of Healthy Aging Study

Score test for age at onset genetic linkage analysis in selected sibling pairs

Genotype-Based Score Test for Association Testing in Families

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