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Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes
AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages...
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
Springer-Verlag
2012
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536959/ https://www.ncbi.nlm.nih.gov/pubmed/23160641 http://dx.doi.org/10.1007/s00125-012-2756-1 |
| _version_ | 1782254827636523008 |
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| author | Albrechtsen, A. Grarup, N. Li, Y. Sparsø, T. Tian, G. Cao, H. Jiang, T. Kim, S. Y. Korneliussen, T. Li, Q. Nie, C. Wu, R. Skotte, L. Morris, A. P. Ladenvall, C. Cauchi, S. Stančáková, A. Andersen, G. Astrup, A. Banasik, K. Bennett, A. J. Bolund, L. Charpentier, G. Chen, Y. Dekker, J. M. Doney, A. S. F. Dorkhan, M. Forsen, T. Frayling, T. M. Groves, C. J. Gui, Y. Hallmans, G. Hattersley, A. T. He, K. Hitman, G. A. Holmkvist, J. Huang, S. Jiang, H. Jin, X. Justesen, J. M. Kristiansen, K. Kuusisto, J. Lajer, M. Lantieri, O. Li, W. Liang, H. Liao, Q. Liu, X. Ma, T. Ma, X. Manijak, M. P. Marre, M. Mokrosiński, J. Morris, A. D. Mu, B. Nielsen, A. A. Nijpels, G. Nilsson, P. Palmer, C. N. A. Rayner, N. W. Renström, F. Ribel-Madsen, R. Robertson, N. Rolandsson, O. Rossing, P. Schwartz, T. W. Slagboom, P. E. Sterner, M. Tang, M. Tarnow, L. Tuomi, T. van’t Riet, E. van Leeuwen, N. Varga, T. V. Vestmar, M. A. Walker, M. Wang, B. Wang, Y. Wu, H. Xi, F. Yengo, L. Yu, C. Zhang, X. Zhang, J. Zhang, Q. Zhang, W. Zheng, H. Zhou, Y. Altshuler, D. ‘t Hart, L. M. Franks, P. W. Balkau, B. Froguel, P. McCarthy, M. I. Laakso, M. Groop, L. Christensen, C. Brandslund, I. Lauritzen, T. Witte, D. R. Linneberg, A. Jørgensen, T. Hansen, T. Wang, J. Nielsen, R. Pedersen, O. |
| author_facet | Albrechtsen, A. Grarup, N. Li, Y. Sparsø, T. Tian, G. Cao, H. Jiang, T. Kim, S. Y. Korneliussen, T. Li, Q. Nie, C. Wu, R. Skotte, L. Morris, A. P. Ladenvall, C. Cauchi, S. Stančáková, A. Andersen, G. Astrup, A. Banasik, K. Bennett, A. J. Bolund, L. Charpentier, G. Chen, Y. Dekker, J. M. Doney, A. S. F. Dorkhan, M. Forsen, T. Frayling, T. M. Groves, C. J. Gui, Y. Hallmans, G. Hattersley, A. T. He, K. Hitman, G. A. Holmkvist, J. Huang, S. Jiang, H. Jin, X. Justesen, J. M. Kristiansen, K. Kuusisto, J. Lajer, M. Lantieri, O. Li, W. Liang, H. Liao, Q. Liu, X. Ma, T. Ma, X. Manijak, M. P. Marre, M. Mokrosiński, J. Morris, A. D. Mu, B. Nielsen, A. A. Nijpels, G. Nilsson, P. Palmer, C. N. A. Rayner, N. W. Renström, F. Ribel-Madsen, R. Robertson, N. Rolandsson, O. Rossing, P. Schwartz, T. W. Slagboom, P. E. Sterner, M. Tang, M. Tarnow, L. Tuomi, T. van’t Riet, E. van Leeuwen, N. Varga, T. V. Vestmar, M. A. Walker, M. Wang, B. Wang, Y. Wu, H. Xi, F. Yengo, L. Yu, C. Zhang, X. Zhang, J. Zhang, Q. Zhang, W. Zheng, H. Zhou, Y. Altshuler, D. ‘t Hart, L. M. Franks, P. W. Balkau, B. Froguel, P. McCarthy, M. I. Laakso, M. Groop, L. Christensen, C. Brandslund, I. Lauritzen, T. Witte, D. R. Linneberg, A. Jørgensen, T. Hansen, T. Wang, J. Nielsen, R. Pedersen, O. |
| author_sort | Albrechtsen, A. |
| collection | PubMed |
| description | AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case–control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. RESULTS: Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(−14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(−11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(−10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-012-2756-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users. |
| format | Online Article Text |
| id | pubmed-3536959 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2012 |
| publisher | Springer-Verlag |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-35369592013-01-04 Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes Albrechtsen, A. Grarup, N. Li, Y. Sparsø, T. Tian, G. Cao, H. Jiang, T. Kim, S. Y. Korneliussen, T. Li, Q. Nie, C. Wu, R. Skotte, L. Morris, A. P. Ladenvall, C. Cauchi, S. Stančáková, A. Andersen, G. Astrup, A. Banasik, K. Bennett, A. J. Bolund, L. Charpentier, G. Chen, Y. Dekker, J. M. Doney, A. S. F. Dorkhan, M. Forsen, T. Frayling, T. M. Groves, C. J. Gui, Y. Hallmans, G. Hattersley, A. T. He, K. Hitman, G. A. Holmkvist, J. Huang, S. Jiang, H. Jin, X. Justesen, J. M. Kristiansen, K. Kuusisto, J. Lajer, M. Lantieri, O. Li, W. Liang, H. Liao, Q. Liu, X. Ma, T. Ma, X. Manijak, M. P. Marre, M. Mokrosiński, J. Morris, A. D. Mu, B. Nielsen, A. A. Nijpels, G. Nilsson, P. Palmer, C. N. A. Rayner, N. W. Renström, F. Ribel-Madsen, R. Robertson, N. Rolandsson, O. Rossing, P. Schwartz, T. W. Slagboom, P. E. Sterner, M. Tang, M. Tarnow, L. Tuomi, T. van’t Riet, E. van Leeuwen, N. Varga, T. V. Vestmar, M. A. Walker, M. Wang, B. Wang, Y. Wu, H. Xi, F. Yengo, L. Yu, C. Zhang, X. Zhang, J. Zhang, Q. Zhang, W. Zheng, H. Zhou, Y. Altshuler, D. ‘t Hart, L. M. Franks, P. W. Balkau, B. Froguel, P. McCarthy, M. I. Laakso, M. Groop, L. Christensen, C. Brandslund, I. Lauritzen, T. Witte, D. R. Linneberg, A. Jørgensen, T. Hansen, T. Wang, J. Nielsen, R. Pedersen, O. Diabetologia Article AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case–control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. RESULTS: Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(−14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(−11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(−10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-012-2756-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Springer-Verlag 2012-11-19 2013 /pmc/articles/PMC3536959/ /pubmed/23160641 http://dx.doi.org/10.1007/s00125-012-2756-1 Text en © The Author(s) 2012 https://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
| spellingShingle | Article Albrechtsen, A. Grarup, N. Li, Y. Sparsø, T. Tian, G. Cao, H. Jiang, T. Kim, S. Y. Korneliussen, T. Li, Q. Nie, C. Wu, R. Skotte, L. Morris, A. P. Ladenvall, C. Cauchi, S. Stančáková, A. Andersen, G. Astrup, A. Banasik, K. Bennett, A. J. Bolund, L. Charpentier, G. Chen, Y. Dekker, J. M. Doney, A. S. F. Dorkhan, M. Forsen, T. Frayling, T. M. Groves, C. J. Gui, Y. Hallmans, G. Hattersley, A. T. He, K. Hitman, G. A. Holmkvist, J. Huang, S. Jiang, H. Jin, X. Justesen, J. M. Kristiansen, K. Kuusisto, J. Lajer, M. Lantieri, O. Li, W. Liang, H. Liao, Q. Liu, X. Ma, T. Ma, X. Manijak, M. P. Marre, M. Mokrosiński, J. Morris, A. D. Mu, B. Nielsen, A. A. Nijpels, G. Nilsson, P. Palmer, C. N. A. Rayner, N. W. Renström, F. Ribel-Madsen, R. Robertson, N. Rolandsson, O. Rossing, P. Schwartz, T. W. Slagboom, P. E. Sterner, M. Tang, M. Tarnow, L. Tuomi, T. van’t Riet, E. van Leeuwen, N. Varga, T. V. Vestmar, M. A. Walker, M. Wang, B. Wang, Y. Wu, H. Xi, F. Yengo, L. Yu, C. Zhang, X. Zhang, J. Zhang, Q. Zhang, W. Zheng, H. Zhou, Y. Altshuler, D. ‘t Hart, L. M. Franks, P. W. Balkau, B. Froguel, P. McCarthy, M. I. Laakso, M. Groop, L. Christensen, C. Brandslund, I. Lauritzen, T. Witte, D. R. Linneberg, A. Jørgensen, T. Hansen, T. Wang, J. Nielsen, R. Pedersen, O. Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes |
| title | Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes |
| title_full | Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes |
| title_fullStr | Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes |
| title_full_unstemmed | Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes |
| title_short | Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes |
| title_sort | exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536959/ https://www.ncbi.nlm.nih.gov/pubmed/23160641 http://dx.doi.org/10.1007/s00125-012-2756-1 |
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