Genome-wide association study of café-au-lait macule number in neurofibromatosis type 1
© Published 2020. This article is a U.S. Government work and is in the public domain in the USA. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC..
BACKGROUND: Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder that arises due to pathogenic variants in tumor suppressor NF1. NF1 has variable expressivity that may be due, at least in part, from heritable elements such as modifier genes; however, few genetic modifiers have been identified to date.
METHODS: In this study, we performed a genome-wide association analysis of the number of café-au-lait macules (CALM) that are considered a tumor-like trait as a clinical phenotype modifying NF1.
RESULTS: A borderline genome-wide significant association was identified in the discovery cohort (CALM1, N = 112) between CALM number and rs12190451 (and rs3799603, r2 = 1.0; p = 7.4 × 10-8 ) in the intronic region of RPS6KA2. Although, this association was not replicated in the second cohort (CALM2, N = 59) and a meta-analysis did not show significantly associated variants in this region, a significant corroboration score (0.72) was obtained for the RPS6KA2 signal in the discovery cohort (CALM1) using Complementary Pairs Stability Selection for Genome-Wide Association Studies (ComPaSS-GWAS) analysis, suggesting that the lack of replication may be due to heterogeneity of the cohorts rather than type I error.
CONCLUSION: rs12190451 is located in a melanocyte-specific enhancer and may influence RPS6KA2 expression in melanocytes-warranting further functional studies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
Molecular genetics & genomic medicine - 8(2020), 10 vom: 02. Okt., Seite e1400 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sung, Heejong [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 31.05.2021 Date Revised 31.05.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/mgg3.1400 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM314425764 |
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| 100 | 1 | |a Sung, Heejong |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Genome-wide association study of café-au-lait macule number in neurofibromatosis type 1 |
| 264 | 1 | |c 2020 | |
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| 500 | |a Date Completed 31.05.2021 | ||
| 500 | |a Date Revised 31.05.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © Published 2020. This article is a U.S. Government work and is in the public domain in the USA. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. | ||
| 520 | |a BACKGROUND: Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder that arises due to pathogenic variants in tumor suppressor NF1. NF1 has variable expressivity that may be due, at least in part, from heritable elements such as modifier genes; however, few genetic modifiers have been identified to date | ||
| 520 | |a METHODS: In this study, we performed a genome-wide association analysis of the number of café-au-lait macules (CALM) that are considered a tumor-like trait as a clinical phenotype modifying NF1 | ||
| 520 | |a RESULTS: A borderline genome-wide significant association was identified in the discovery cohort (CALM1, N = 112) between CALM number and rs12190451 (and rs3799603, r2 = 1.0; p = 7.4 × 10-8 ) in the intronic region of RPS6KA2. Although, this association was not replicated in the second cohort (CALM2, N = 59) and a meta-analysis did not show significantly associated variants in this region, a significant corroboration score (0.72) was obtained for the RPS6KA2 signal in the discovery cohort (CALM1) using Complementary Pairs Stability Selection for Genome-Wide Association Studies (ComPaSS-GWAS) analysis, suggesting that the lack of replication may be due to heterogeneity of the cohorts rather than type I error | ||
| 520 | |a CONCLUSION: rs12190451 is located in a melanocyte-specific enhancer and may influence RPS6KA2 expression in melanocytes-warranting further functional studies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Intramural | |
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| 650 | 4 | |a complementary pairs stability selection for genome-wide association studies analysis | |
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| 700 | 1 | |a Pemov, Alexander |e verfasserin |4 aut | |
| 700 | 1 | |a Sabourin, Jeremy A |e verfasserin |4 aut | |
| 700 | 1 | |a Baldwin, Andrea M |e verfasserin |4 aut | |
| 700 | 1 | |a Bass, Sara |e verfasserin |4 aut | |
| 700 | 1 | |a Teshome, Kedest |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Wen |e verfasserin |4 aut | |
| 700 | 0 | |a Frederick National Laboratory for Cancer Research |e verfasserin |4 aut | |
| 700 | 1 | |a Widemann, Brigitte C |e verfasserin |4 aut | |
| 700 | 1 | |a Stewart, Douglas R |e verfasserin |4 aut | |
| 700 | 1 | |a Wilson, Alexander F |e verfasserin |4 aut | |
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