期刊
HUMAN GENETICS
卷 137, 期 10, 页码 795-806出版社
SPRINGER
DOI: 10.1007/s00439-018-1938-4
关键词
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资金
- NHGRI [HG-004738]
- NCI Clinical Sequencing Exploratory Research program [UO1 HG006507, HG007307]
- National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, HHSN268201600004C, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]
- National Heart, Lung, and Blood Institute (NHLBI)
- WHI [X01-HG006196]
- NHLBI [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924, RC2 HL-102925, RC2 HL-102926, HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HHSN268201200036C, HHSN268200800007C]
- Seattle Tumor Translational Research Program
- Cottrell Family Fund
- NINDS
- NIA [AG-023629, AG-15928, AG-20098, AG-027058, AG08122, AG033193]
- National Institute on Minority Health and Health Disparities [N01 HC-95170, N01 HC-95171, N01 HC-95172]
- Cystic Fibrosis (CF)
- Cystic Fibrosis Foundation [GIB-SON07K0, KNOWLE00A0, OBSERV04K0, RDP R026]
- NIH National Center for Research Resources [UL1 RR-025014]
- National Human Genome Research Institute (NHGRI) [5R00 HG-004316]
- COPD Foundation
- NHLBI Division of Lung Diseases [HR-46002]
- NIH [P50 HL-084946, K23 AR-52742, HL-077916, HL-69197, HL-76285, M01 RR-07122]
- National Institute of Neurological Disorders and Stroke (NINDS) [R01 NS039987]
- NINDS [R01 NS042733]
- National Heart, Lung, and Blood Institute [HL-102924]
- National Institutes of Health (NIH), U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]
- The NHLBI [HL080295, N01-HC95095, N01-HC48047, N01-HC48048, N01-HC48049, N01-HC48050, N01-HC-25195, R01 NS17950, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]
- A NHLBI [N01-HC-85239, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, R02 HL-095396, U01 HL-089897, U01 HL-089856]
- [2P30CA015704-40]
- [RO1CA194663]
- [RO1CA189184]
- [UO1152756]
- [RR-024156]
- [R01 HL-068890]
- [RC2 HL-101779]
- [RC2 HL-066583]
- [F32 HL-083714]
- [RC2 HL-101651]
Although similar to 25% of colorectal cancer or polyp (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk-associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. We found a significant enrichment of PDVs in cases vs. controls: 20% of cases vs. 11.5% of controls with 1 PDV (OR=1.9, p=0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p=0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p=0.0001), BRCA2 (p=0.01) and BRIP1 (p=0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P.
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