Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes

Anders Albrechtsen; Niels Grarup; Y. Li; Thomas Hempel Sparsø; G. Tian; H. Cao; T. Jiang; S.Y. Kim; Thorfinn Sand Korneliussen; Q. Li; C. Nie; R. Wu; Line Skotte; A.P. Morris; C. Ladenvall; S. Cauchi; A. Stancáková; G. Andersen; Arne Astrup; Karina Banasik; A.J. Bennett; Lars Bolund; G. Charpentier; Y. Chen; J.M. Dekker; A.S.F. Doney; M. Dorkhan; T. Forsen; T.M. Frayling; C.J. Groves; Y. Gui; G. Hallmans; A.T. Hattersley; K. He; G.A. Hitman; J. Holmkvist; S. Huang; H. Jiang; X. Jin; Johanne Marie Justesen; Karsten Kristiansen; J. Kuusisto; M. Lajer; O. Lantieri; W. Li; H. Liang; Q. Liao; X. Liu; T. Ma; X. Ma; M.P. Manijak; M. Marre; Jacek Mokrosinski; A.D. Morris; B. Mu; A.A. Nielsen; G. Nijpels; P. Nilsson; C.N.A. Palmer; N.W. Rayner; F. Renström; Rasmus Ribel-Madsen; N. Robertson; O. Rolandsson; P. Rossing; Thue W. Schwartz; P.E. Slagboom; M. Sterner; M. Tang; L. Tarnow; T. Tuomi; E. Van't Riet; N. van Leeuwen; T.V. Varga; Marie Aare Vestmar; M. Walker; B. Wang; Y. Wang; H. Wu; F. Xi; L. Yengo; C. Yu; X. Zhang; J. Zhang; Q. Zhang; W. Zhang; H. Zheng; Y. Zhou; D. Altshuler; L.M. 't Hart; P.W. Franks; B. Balkau; P. Froguel; M.I. McCarthy; M. Laakso; L. Groop; C. Christensen; I. Brandslund; T. Lauritzen; D.R. Witte; A. Linneberg; Torben Jørgensen; Torben Hansen; Jun Wang; Rasmus Nielsen; Oluf Pedersen

doi:10.1007/s00125-012-2756-1

Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes

Anders Albrechtsen, Niels Grarup, Y. Li, Thomas Hempel Sparsø, G. Tian, H. Cao, T. Jiang, S.Y. Kim, Thorfinn Sand Korneliussen, Q. Li, C. Nie, R. Wu, Line Skotte, A.P. Morris, C. Ladenvall, S. Cauchi, A. Stancáková, G. Andersen, Arne Astrup, Karina BanasikA.J. Bennett, Lars Bolund, G. Charpentier, Y. Chen, J.M. Dekker, A.S.F. Doney, M. Dorkhan, T. Forsen, T.M. Frayling, C.J. Groves, Y. Gui, G. Hallmans, A.T. Hattersley, K. He, G.A. Hitman, J. Holmkvist, S. Huang, H. Jiang, X. Jin, Johanne Marie Justesen, Karsten Kristiansen, J. Kuusisto, M. Lajer, O. Lantieri, W. Li, H. Liang, Q. Liao, X. Liu, T. Ma, X. Ma, M.P. Manijak, M. Marre, Jacek Mokrosinski, A.D. Morris, B. Mu, A.A. Nielsen, G. Nijpels, P. Nilsson, C.N.A. Palmer, N.W. Rayner, F. Renström, Rasmus Ribel-Madsen, N. Robertson, O. Rolandsson, P. Rossing, Thue W. Schwartz, P.E. Slagboom, M. Sterner, M. Tang, L. Tarnow, T. Tuomi, E. Van't Riet, N. van Leeuwen, T.V. Varga, Marie Aare Vestmar, M. Walker, B. Wang, Y. Wang, H. Wu, F. Xi, L. Yengo, C. Yu, X. Zhang, J. Zhang, Q. Zhang, W. Zhang, H. Zheng, Y. Zhou, D. Altshuler, L.M. 't Hart, P.W. Franks, B. Balkau, P. Froguel, M.I. McCarthy, M. Laakso, L. Groop, C. Christensen, I. Brandslund, T. Lauritzen, D.R. Witte, A. Linneberg, Torben Jørgensen, Torben Hansen, Jun Wang, Rasmus Nielsen, Oluf Pedersen

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Abstract

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¿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.

Original language	English
Journal	Diabetologia
Volume	56
Issue number	2
Pages (from-to)	298-310
Number of pages	13
ISSN	0012-186X
DOIs	https://doi.org/10.1007/s00125-012-2756-1
Publication status	Published - Feb 2013

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Albrechtsen, A., Grarup, N., Li, Y., Sparsø, T. H., Tian, G., Cao, H., Jiang, T., Kim, S. Y., Korneliussen, T. S., Li, Q., Nie, C., Wu, R., Skotte, L., Morris, A. P., Ladenvall, C., Cauchi, S., Stancáková, A., Andersen, G., Astrup, A., ... Pedersen, O. (2013). Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes. Diabetologia, 56(2), 298-310. https://doi.org/10.1007/s00125-012-2756-1

Albrechtsen, A , Grarup, N, Li, Y, Sparsø, TH, Tian, G, Cao, H, Jiang, T, Kim, SY, Korneliussen, TS, Li, Q, Nie, C, Wu, R, Skotte, L, Morris, AP, Ladenvall, C, Cauchi, S, Stancáková, A, Andersen, G, Astrup, A, Banasik, K, Bennett, AJ, Bolund, L, Charpentier, G, Chen, Y, Dekker, JM, Doney, ASF, Dorkhan, M, Forsen, T, Frayling, TM, Groves, CJ, Gui, Y, Hallmans, G, Hattersley, AT, He, K, Hitman, GA, Holmkvist, J, Huang, S, Jiang, H, Jin, X, Justesen, JM , Kristiansen, K, Kuusisto, J, Lajer, M, Lantieri, O, Li, W, Liang, H, Liao, Q, Liu, X, Ma, T, Ma, X, Manijak, MP, Marre, M, Mokrosinski, J, Morris, AD, Mu, B, Nielsen, AA, Nijpels, G, Nilsson, P, Palmer, CNA, Rayner, NW, Renström, F, Ribel-Madsen, R, Robertson, N, Rolandsson, O, Rossing, P, Schwartz, TW, Slagboom, PE, Sterner, M, Tang, M, Tarnow, L, Tuomi, T, Van't Riet, E, van Leeuwen, N, Varga, TV, Vestmar, MA, 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, LM, Franks, PW, Balkau, B, Froguel, P, McCarthy, MI, Laakso, M, Groop, L, Christensen, C, Brandslund, I, Lauritzen, T, Witte, DR, Linneberg, A, Jørgensen, T, Hansen, T, Wang, J, Nielsen, R & Pedersen, O 2013, 'Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes', Diabetologia, vol. 56, no. 2, pp. 298-310. https://doi.org/10.1007/s00125-012-2756-1

@article{900595375135465dbc264eb904554ca2,

title = "Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes",

abstract = "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¿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.",

author = "Anders Albrechtsen and Niels Grarup and Y. Li and Spars{\o}, {Thomas Hempel} and G. Tian and H. Cao and T. Jiang and S.Y. Kim and Korneliussen, {Thorfinn Sand} and Q. Li and C. Nie and R. Wu and Line Skotte and A.P. Morris and C. Ladenvall and S. Cauchi and A. Stanc{\'a}kov{\'a} and G. Andersen and Arne Astrup and Karina Banasik and A.J. Bennett and Lars Bolund and G. Charpentier and Y. Chen and J.M. Dekker and A.S.F. Doney and M. Dorkhan and T. Forsen and T.M. Frayling and C.J. Groves and Y. Gui and G. Hallmans and A.T. Hattersley and K. He and G.A. Hitman and J. Holmkvist and S. Huang and H. Jiang and X. Jin and Justesen, {Johanne Marie} and Karsten Kristiansen and J. Kuusisto and M. Lajer and O. Lantieri and W. Li and H. Liang and Q. Liao and X. Liu and T. Ma and X. Ma and M.P. Manijak and M. Marre and Jacek Mokrosinski and A.D. Morris and B. Mu and A.A. Nielsen and G. Nijpels and P. Nilsson and C.N.A. Palmer and N.W. Rayner and F. Renstr{\"o}m and Rasmus Ribel-Madsen and N. Robertson and O. Rolandsson and P. Rossing and Schwartz, {Thue W.} and P.E. Slagboom and M. Sterner and M. Tang and L. Tarnow and T. Tuomi and {Van't Riet}, E. and {van Leeuwen}, N. and T.V. Varga and Vestmar, {Marie Aare} and M. Walker and B. Wang and Y. Wang and H. Wu and F. Xi and L. Yengo and C. Yu and X. Zhang and J. Zhang and Q. Zhang and W. Zhang and H. Zheng and Y. Zhou and D. Altshuler and {'t Hart}, L.M. and P.W. Franks and B. Balkau and P. Froguel and M.I. McCarthy and M. Laakso and L. Groop and C. Christensen and I. Brandslund and T. Lauritzen and D.R. Witte and A. Linneberg and Torben J{\o}rgensen and Torben Hansen and Jun Wang and Rasmus Nielsen and Oluf Pedersen",

note = "CURIS 2013 NEXS 069",

year = "2013",

month = feb,

doi = "10.1007/s00125-012-2756-1",

language = "English",

volume = "56",

pages = "298--310",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer",

number = "2",

}

TY - JOUR

T1 - Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes

AU - Albrechtsen, Anders

AU - Grarup, Niels

AU - Li, Y.

AU - Sparsø, Thomas Hempel

AU - Tian, G.

AU - Cao, H.

AU - Jiang, T.

AU - Kim, S.Y.

AU - Korneliussen, Thorfinn Sand

AU - Li, Q.

AU - Nie, C.

AU - Wu, R.

AU - Skotte, Line

AU - Morris, A.P.

AU - Ladenvall, C.

AU - Cauchi, S.

AU - Stancáková, A.

AU - Andersen, G.

AU - Astrup, Arne

AU - Banasik, Karina

AU - Bennett, A.J.

AU - Bolund, Lars

AU - Charpentier, G.

AU - Chen, Y.

AU - Dekker, J.M.

AU - Doney, A.S.F.

AU - Dorkhan, M.

AU - Forsen, T.

AU - Frayling, T.M.

AU - Groves, C.J.

AU - Gui, Y.

AU - Hallmans, G.

AU - Hattersley, A.T.

AU - He, K.

AU - Hitman, G.A.

AU - Holmkvist, J.

AU - Huang, S.

AU - Jiang, H.

AU - Jin, X.

AU - Justesen, Johanne Marie

AU - Kristiansen, Karsten

AU - Kuusisto, J.

AU - Lajer, M.

AU - Lantieri, O.

AU - Li, W.

AU - Liang, H.

AU - Liao, Q.

AU - Liu, X.

AU - Ma, T.

AU - Ma, X.

AU - Manijak, M.P.

AU - Marre, M.

AU - Mokrosinski, Jacek

AU - Morris, A.D.

AU - Mu, B.

AU - Nielsen, A.A.

AU - Nijpels, G.

AU - Nilsson, P.

AU - Palmer, C.N.A.

AU - Rayner, N.W.

AU - Renström, F.

AU - Ribel-Madsen, Rasmus

AU - Robertson, N.

AU - Rolandsson, O.

AU - Rossing, P.

AU - Schwartz, Thue W.

AU - Slagboom, P.E.

AU - Sterner, M.

AU - Tang, M.

AU - Tarnow, L.

AU - Tuomi, T.

AU - Van't Riet, E.

AU - van Leeuwen, N.

AU - Varga, T.V.

AU - Vestmar, Marie Aare

AU - Walker, M.

AU - Wang, B.

AU - Wang, Y.

AU - Wu, H.

AU - Xi, F.

AU - Yengo, L.

AU - Yu, C.

AU - Zhang, X.

AU - Zhang, J.

AU - Zhang, Q.

AU - Zhang, W.

AU - Zheng, H.

AU - Zhou, Y.

AU - Altshuler, D.

AU - 't Hart, L.M.

AU - Franks, P.W.

AU - Balkau, B.

AU - Froguel, P.

AU - McCarthy, M.I.

AU - Laakso, M.

AU - Groop, L.

AU - Christensen, C.

AU - Brandslund, I.

AU - Lauritzen, T.

AU - Witte, D.R.

AU - Linneberg, A.

AU - Jørgensen, Torben

AU - Hansen, Torben

AU - Wang, Jun

AU - Nielsen, Rasmus

AU - Pedersen, Oluf

N1 - CURIS 2013 NEXS 069

PY - 2013/2

Y1 - 2013/2

N2 - 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¿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.

AB - 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¿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.

U2 - 10.1007/s00125-012-2756-1

DO - 10.1007/s00125-012-2756-1

M3 - Journal article

C2 - 23160641

SN - 0012-186X

VL - 56

SP - 298

EP - 310

JO - Diabetologia

JF - Diabetologia

IS - 2

ER -

Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes

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