Contribution of Common Genetic Variants to Familial Aggregation of Disease and Implications for Sequencing Studies
Open Access
- 15 November 2019
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Genetics
- Vol. 15 (11), e1008490
- https://doi.org/10.1371/journal.pgen.1008490
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. Multiple members in a family can be diagnosed with the same disease. In such families, genetics may be a significant factor in disease risk. However, it remains unclear whether such familial aggregation of disease is likely due to a single highly penetrant rare variant (HPRV), 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 introduce a related statistic that can be used to select families for sequencing studies trying to identify HPRV.Funding Information
- Fondo de Investigaciones Sanitarias (PI12/00840, PI15/00956, PI15/00716)
- Fundació La Marató (201331‐30)
- European Commission (LSHC‐CT‐2006‐018702)
- Fundación Científica Asociación Española Contra el Cáncer (GCB15152978SOEN)
- European Academy of Dermatology and Venereology (PPRC‐2017/19)
- Italian Ministry of Health (RF-2016-02362288)
This publication has 24 references indexed in Scilit:
- Genetic Complexity of Crohn’s Disease in Two Large Ashkenazi Jewish FamiliesGastroenterology, 2016
- The Contribution of GWAS Loci in Familial DyslipidemiasPLoS Genetics, 2016
- Breast cancer risk prediction using a polygenic risk score in the familial setting: a prospective study from the Breast Cancer Family Registry and kConFabGenetics in Medicine, 2016
- Prevalence ofMITFp.E318K in Patients With Melanoma Independent of the Presence ofCDKN2ACausative MutationsJAMA Dermatology, 2016
- Update in genetic susceptibility in melanoma2015
- Rare missense variants in POT1 predispose to familial cutaneous malignant melanomaNature Genetics, 2014
- Using Genetic Prediction from Known Complex Disease Loci to Guide the Design of Next-Generation Sequencing ExperimentsPLOS ONE, 2013
- A Role for Common Genomic Variants in the Assessment of Familial Breast CancerJournal of Clinical Oncology, 2012
- Genetic susceptibility in familial melanoma from northeastern ItalyJournal of Medical Genetics, 2004
- On the Use of Familial Aggregation in Population-Based Case Probands for Calculating PenetranceJNCI Journal of the National Cancer Institute, 2002