Abstract:
:Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Thomas M,Sakoda LC,Hoffmeister M,Rosenthal EA,Lee JK,van Duijnhoven FJB,Platz EA,Wu AH,Dampier CH,de la Chapelle A,Wolk A,Joshi AD,Burnett-Hartman A,Gsur A,Lindblom A,Castells A,Win AK,Namjou B,Van Guelpen B,Tangendoi
10.1016/j.ajhg.2020.07.006subject
Has Abstractpub_date
2020-09-03 00:00:00pages
432-444issue
3eissn
0002-9297issn
1537-6605pii
S0002-9297(20)30236-6journal_volume
107pub_type
杂志文章abstract::A genetical model is found to provide a good fit to family data on vitiligo. The model postulates that recessive alleles at a set of four unlinked diallelic loci are involved in the causation of the disorder. Under this multiple recessive homozygosis model, for normal X affected families ascertained through the affect...
journal_title:American journal of human genetics
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abstract::We have shown functional complementation of a genetic deficiency in human cultured cells, using artificial chromosomes derived from cloned human genomic fragments. A 404-kb human-artificial-chromosome (HAC) vector, consisting of 220 kb of alphoid DNA from the centromere of chromosome 17, human telomeres, and the hypox...
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journal_title:American journal of human genetics
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journal_title:American journal of human genetics
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journal_title:American journal of human genetics
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doi:
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journal_title:American journal of human genetics
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doi:
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doi:10.1086/508572
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journal_title:American journal of human genetics
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doi:10.1086/302786
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journal_title:American journal of human genetics
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journal_title:American journal of human genetics
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journal_title:American journal of human genetics
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doi:
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journal_title:American journal of human genetics
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journal_title:American journal of human genetics
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doi:
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journal_title:American journal of human genetics
pub_type: 杂志文章
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更新日期:1988-10-01 00:00:00