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

English version

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
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1008490

Souhrn

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:

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

Zdroje

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