Contribution of Common Genetic Variants to Familial Aggregation of Disease and Implications for Sequencing Studies

Andrew Schlafly, Ruth M. Pfeiffer, Eduardo Nagore, Susana Puig, Donato Calista, Paola Ghiorzo, Chiara Menin, Maria Concetta Fargnoli, Ketty Peris, Lei Song, Tongwu Zhang, Jianxin Shi, Maria Teresa Landi, Joshua Neil Sampson

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Article numbere1008490
Pages (from-to)1-15
Number of pages15
JournalPLoS Genetics
Issue number11
Publication statusPublished - Nov 1 2019


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