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, T Korneliussen, Q Li, C Nie, R Wu, Line Skotte, A P Morris, C Ladenvall, S Cauchi, A Stančáková, G Andersen, A Astrup, Karina Banasik & 31 andre A J Bennett, L 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, J M Justesen, K Kristiansen, J Kuusisto, M Lajer, O Lantieri, W Li, Hong Liang, Q Liao, A A Nielsen, C Christensen, I Brandslund, D.E.S.I.R. Study Group

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.
OriginalsprogEngelsk
TidsskriftDiabetologia
Vol/bind56
Udgave nummer2
Sider (fra-til)298-310
Antal sider13
ISSN0012-186X
DOI
StatusUdgivet - 2013

Fingeraftryk

Exome
Type 2 Diabetes Mellitus
HDL Cholesterol
Meta-Analysis
Fasting

Citer dette

Albrechtsen, A., Grarup, N., Li, Y., Sparsø, T. H., Tian, G., Cao, H., ... D.E.S.I.R. Study Group (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, Anders ; Grarup, Niels ; Li, Y ; Sparsø, Thomas Hempel ; Tian, G ; Cao, H ; Jiang, T ; Kim, S Y ; Korneliussen, T ; Li, Q ; Nie, C ; Wu, R ; Skotte, Line ; Morris, A P ; Ladenvall, C ; Cauchi, S ; Stančáková, A ; Andersen, G ; Astrup, A ; Banasik, Karina ; 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, Hong ; Liao, Q ; Nielsen, A A ; Christensen, C ; Brandslund, I ; D.E.S.I.R. Study Group. / Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes. I: Diabetologia. 2013 ; Bind 56, Nr. 2. s. 298-310.
@article{4746e5fbbce14cd08d9ae6fe9e90a4b1,
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 Kim, {S Y} and T Korneliussen and Q Li and C Nie and R Wu and Line Skotte and Morris, {A P} and C Ladenvall and S Cauchi and A Stanč{\'a}kov{\'a} and G Andersen and A Astrup and Karina Banasik and Bennett, {A J} and L Bolund and G Charpentier and Y Chen and Dekker, {J M} and Doney, {A S F} and M Dorkhan and T Forsen and Frayling, {T M} and Groves, {C J} and Y Gui and G Hallmans and Hattersley, {A T} and K He and Hitman, {G A} and J Holmkvist and S Huang and H Jiang and X Jin and Justesen, {J M} and K Kristiansen and J Kuusisto and M Lajer and O Lantieri and W Li and Hong Liang and Q Liao and Nielsen, {A A} and C Christensen and I Brandslund and {D.E.S.I.R. Study Group}",
year = "2013",
doi = "10.1007/s00125-012-2756-1",
language = "English",
volume = "56",
pages = "298--310",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Heinemann",
number = "2",

}

Albrechtsen, A, Grarup, N, Li, Y, Sparsø, TH, Tian, G, Cao, H, Jiang, T, Kim, SY, Korneliussen, T, Li, Q, Nie, C, Wu, R, Skotte, L, Morris, AP, Ladenvall, C, Cauchi, S, Stančáková, 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, Nielsen, AA, Christensen, C, Brandslund, I & D.E.S.I.R. Study Group 2013, 'Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes', Diabetologia, bind 56, nr. 2, s. 298-310. https://doi.org/10.1007/s00125-012-2756-1

Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes. / Albrechtsen, Anders; Grarup, Niels; Li, Y; Sparsø, Thomas Hempel; Tian, G; Cao, H; Jiang, T; Kim, S Y; Korneliussen, T; Li, Q; Nie, C; Wu, R; Skotte, Line; Morris, A P; Ladenvall, C; Cauchi, S; Stančáková, A; Andersen, G; Astrup, A; Banasik, Karina; 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, Hong; Liao, Q; Nielsen, A A; Christensen, C; Brandslund, I; D.E.S.I.R. Study Group.

I: Diabetologia, Bind 56, Nr. 2, 2013, s. 298-310.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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, T

AU - Li, Q

AU - Nie, C

AU - Wu, R

AU - Skotte, Line

AU - Morris, A P

AU - Ladenvall, C

AU - Cauchi, S

AU - Stančáková, A

AU - Andersen, G

AU - Astrup, A

AU - Banasik, Karina

AU - Bennett, A J

AU - Bolund, L

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, J M

AU - Kristiansen, K

AU - Kuusisto, J

AU - Lajer, M

AU - Lantieri, O

AU - Li, W

AU - Liang, Hong

AU - Liao, Q

AU - Nielsen, A A

AU - Christensen, C

AU - Brandslund, I

AU - D.E.S.I.R. Study Group

PY - 2013

Y1 - 2013

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

VL - 56

SP - 298

EP - 310

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 2

ER -