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:
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:
Alleles – Consortia – Epidemiology – Genetics of disease – Genotyping – Heredity – Melanomas – Test statistics
Zdroje
1. Khoury MJ, Beaty TH, Liang KY. Can Familial Aggregation of Disease Be Explained by Familial Aggregation of Environmental Risk-Factors. Am J Epidemiol. 1988;127(3):674–83. PubMed PMID: WOS:A1988M162600023. doi: 10.1093/oxfordjournals.aje.a114842 3341366
2. Online Mendelian Inheritance in Man, OMIM McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD) [12/12/2018]. Available from: https://omim.org/.
3. Khera AV, Chaffin M, Aragam KG, Haas ME, Roselli C, Choi SH, et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. 2018;50(9):1219-+. PubMed PMID: WOS:000443151300011. doi: 10.1038/s41588-018-0183-z 30104762
4. Potrony M, Puig-Butille JA, Aguilera P, Badenas C, Tell-Marti G, Carrera C, et al. Prevalence of MITF p.E318K in Patients With Melanoma Independent of the Presence of CDKN2A Causative Mutations. Jama Dermatol. 2016;152(4):405–12. PubMed PMID: WOS:000373916600012. doi: 10.1001/jamadermatol.2015.4356 26650189
5. Speed D, Cai N, Johnson MR, Nejentsev S, Balding DJ, Consortium U. Reevaluation of SNP heritability in complex human traits. Nat Genet. 2017;49(7):986-+. PubMed PMID: WOS:000404253300006. doi: 10.1038/ng.3865 28530675
6. Gormley P, Kurki MI, Hiekkala ME, Veerapen K, Happola P, Mitchell AA, et al. Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families (vol 98, pg 743, 2018). Neuron. 2018;99(5):1098-. PubMed PMID: WOS:000443712200015. doi: 10.1016/j.neuron.2018.08.029 30189203
7. Jarauta E, Perez-Ruiz MR, Perez-Calahorra S, Mateo-Gallego R, Cenarro A, Cofan M, et al. Lipid phenotype and heritage pattern in families with genetic hypercholesterolemia not related to LDLR, APOB, PCSK9, or APOE. J Clin Lipidol. 2016;10(6):1397–405. PubMed PMID: WOS:000390829400015. doi: 10.1016/j.jacl.2016.09.011 27919357
8. Ripatti P, Ramo JT, Soderlund S, Surakka I, Matikainen N, Pirinen M, et al. The Contribution of GWAS Loci in Familial Dyslipidemias. Plos Genet. 2016;12(5). PubMed PMID: WOS:000377197100067.
9. Levine AP, Pontikos N, Schiff ER, Jostins L, Speed D, Lovat LB, et al. Genetic Complexity of Crohn's Disease in Two Large Ashkenazi Jewish Families. Gastroenterology. 2016;151(4):698–709. PubMed PMID: WOS:000389548500027. doi: 10.1053/j.gastro.2016.06.040 27373512
10. Tosto G, Bird TD, Tsuang D, Bennett DA, Boeve BF, Cruchaga C, et al. Polygenic risk scores in familial Alzheimer disease. Neurology. 2017;88(12):1180–6. PubMed PMID: WOS:000397383000018. doi: 10.1212/WNL.0000000000003734 28213371
11. Boies S, Merette C, Paccalet T, Maziade M, Bureau A. Polygenic risk scores distinguish patients from non-affected adult relatives and from normal controls in schizophrenia and bipolar disorder multi-affected kindreds. Am J Med Genet B. 2018;177(3):329–36. PubMed PMID: WOS:000427234000005.
12. Kuchenbaecker KB, McGuffog L, Barrowdale D, Lee A, Soucy P, Dennis J, et al. Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers. Jnci-J Natl Cancer I. 2017;109(7). PubMed PMID: WOS:000405496200004.
13. Li HY, Feng BJ, Miron A, Chen XQ, Beesley J, Bimeh E, et al. Breast cancer risk prediction using a polygenic risk score in the familial setting: a prospective study from the Breast Cancer Family Registry and kConFab. Genet Med. 2017;19(1):30–5. PubMed PMID: WOS:000391911100005. doi: 10.1038/gim.2016.43 27171545
14. Muranen TA, Mavaddat N, Khan S, Fagerholm R, Pelttari L, Lee A, et al. Polygenic risk score is associated with increased disease risk in 52 Finnish breast cancer families. Breast Cancer Res Tr. 2016;158(3):463–9. PubMed PMID: WOS:000380711700006.
15. Sawyer S, Mitchell G, McKinley J, Chenevix-Trench G, Beesley J, Chen XQ, et al. A Role for Common Genomic Variants in the Assessment of Familial Breast Cancer. J Clin Oncol. 2012;30(35):4330–6. PubMed PMID: WOS:000312195900014. doi: 10.1200/JCO.2012.41.7469 23109704
16. Begg CB. On the use of familial aggregation in population-based case probands for calculating penetrance. J Natl Cancer I. 2002;94(16):1221–6. PubMed PMID: WOS:000177474200011.
17. Jostins L, Levine AP, Barrett JC. Using Genetic Prediction from Known Complex Disease Loci to Guide the Design of Next-Generation Sequencing Experiments. Plos One. 2013;8(10). PubMed PMID: WOS:000326029300022.
18. Ward WF, JM. Cutaneous Melanoma: Etiology and Therapy. Brisbane, AU: Codon Publications; 2017.
19. Wright S. The results of crosses between inbred strains of guinea pigs, differing in number of digits. Genetics. 1934;19(6):0537–51. PubMed PMID: WOS:000201599900003.
20. Shi JX, Yang XHR, Ballew B, Rotunno M, Calista D, Fargnoli MC, et al. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat Genet. 2014;46(5):482–6. PubMed PMID: WOS:000335422900016. doi: 10.1038/ng.2941 24686846
21. Landi MT, Goldstein AM, Tsang S, Munroe D, Modi W, Ter-Minassian M, et al. Genetic susceptibility in familial melanoma from northeastern Italy. J Med Genet. 2004;41(7):557–66. Epub 2004/07/06. doi: 10.1136/jmg.2003.016907 15235029; PubMed Central PMCID: PMC1735833.
22. Gu FY, Chen TH, Pfeiffer RM, Fargnoli MC, Calista D, Ghiorzo P, et al. Combining common genetic variants and non-genetic risk factors to predict risk of cutaneous melanoma. Hum Mol Genet. 2018;27(23):4145–56. PubMed PMID: WOS:000452536200012. doi: 10.1093/hmg/ddy282 30060076
23. Potrony M, Badenas C, Aguilera P, Puig-Butille JA, Carrera C, Malvehy J, et al. Update in genetic susceptibility in melanoma. Ann Transl Med. 2015;3(15):210. Epub 2015/10/22. doi: 10.3978/j.issn.2305-5839.2015.08.11 26488006; PubMed Central PMCID: PMC4583600.
Štítky
Genetika Reprodukční medicínaČlánek vyšel v časopise
PLOS Genetics
2019 Číslo 11
- Primární hyperoxalurie – aktuální možnosti diagnostiky a léčby
- Srdeční frekvence embrya může být faktorem užitečným v předpovídání výsledku IVF
- Akutní intermitentní porfyrie
- Vztah užívání alkoholu a mužské fertility
- Šanci na úspěšný průběh těhotenství snižují nevhodné hladiny progesteronu vznikající při umělém oplodnění
Nejčtenější v tomto čísle
- The genetic architecture of helminth-specific immune responses in a wild population of Soay sheep (Ovis aries)
- A circadian output center controlling feeding:Fasting rhythms in Drosophila
- AMPK regulates ESCRT-dependent microautophagy of proteasomes concomitant with proteasome storage granule assembly during glucose starvation
- Chromatin dynamics enable transcriptional rhythms in the cnidarian Nematostella vectensis