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

Autoři: Andrew Schlafly aff001;  Ruth M. Pfeiffer aff003;  Eduardo Nagore aff004;  Susana Puig aff005;  Donato Calista aff006;  Paola Ghiorzo aff007;  Chiara Menin aff008;  Maria Concetta Fargnoli aff009;  Ketty Peris aff010;  Lei Song aff003;  Tongwu Zhang aff001;  Jianxin Shi aff003;  Maria Teresa Landi aff001;  Joshua Neil Sampson aff003
Působiště autorů: Integrative Tumor Epidemiology Branch: Division of Cancer Epidemiology and GeneticsNational Cancer Institute, Rockville, Maryland, United States of America aff001;  Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff002;  Biostatistics Branch: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America aff003;  Department of Dermatology, Instituto Valenciano de Oncología, València, Spain aff004;  Dermatology Department, Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain aff005;  Department of Dermatology, Maurizio Bufalini Hospital, Cesena, Italy aff006;  Genetics of Rare Cancers, Department of Internal Medicine (DiMI), University of Genoa and Ospedale Policlinico San Martino Genoa, Genoa, Italy aff007;  Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV—IRCCS, Padua, Italy aff008;  Department of Dermatology, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy aff009;  Institute of Dermatology, Catholic University, Rome, Italy aff010;  Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy aff011
Vyšlo v časopise: Contribution of Common Genetic Variants to Familial Aggregation of Disease and Implications for Sequencing Studies. PLoS Genet 15(11): e32767. doi:10.1371/journal.pgen.1008490
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008490


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.

Klíčová slova:

Alleles – Consortia – Epidemiology – Genetics of disease – Genotyping – Heredity – Melanomas – Test statistics


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Genetika Reprodukční medicína

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PLOS Genetics

2019 Číslo 11

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