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Title: Contribution of Common Genetic Variants to Familial Aggregation of Disease and Implications for Sequencing Studies
Author: Schlafly, Andrew
Pfeiffer, Rurh M.
Nagore, Eduardo
Puig i Sardà, Susana
Calista, Donato
Ghiorzo, Paola
Menin, Chiara
Fargnoli, Maria Concetta
Peris, Ketty
Song, Lei
Zhang, Tongwu
Shi, Jianxin
Landi, Maria Teresa
Sampson, Joshua Neil
Keywords: Càncer
Factors de risc en les malalties
Epidemiologia genètica
Risk factors in diseases
Genetic epidemiology
Issue Date: 15-Nov-2019
Publisher: Public Library of Science (PLoS)
Abstract: Despite genetics being accepted as the primary cause of familial aggregation for most diseases, it is still unclear whether afflicted families are likely to share a single highly penetrant rare variant, many minimally penetrant common variants, or a combination of the two types of variants. We therefore use recent estimates of SNP heritability and the liability threshold model to estimate the proportion of afflicted families likely to carry a rare, causal variant. We then show that Polygenic Risk Scores (PRS) may be useful for identifying families likely to carry such a rare variant and therefore for prioritizing families to include in sequencing studies with that aim. Specifically, we introduce a new statistic that estimates the proportion of individuals carrying causal rare variants based on the family structure, disease pattern, and PRS of genotyped individuals. Finally, we consider data from the MelaNostrum consortium and show that, despite an estimated PRS heritability of only 0.05 for melanoma, families carrying putative causal variants had a statistically significantly lower PRS, supporting the idea that PRS prioritization may be a useful future tool. However, it will be important to evaluate whether the presence of rare mendelian variants are generally associated with the proposed test statistic or lower PRS in future and larger studies.
Note: Reproducció del document publicat a:
It is part of: PLoS Genetics, 2019, vol. 15, num. 11, p. e1008490
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ISSN: 1553-7390
Appears in Collections:Articles publicats en revistes (Medicina)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

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