Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes

Valgerdur Steinthorsdottir; Gudmar Thorleifsson; Patrick Sulem; Hannes Helgason; Niels Grarup; Asgeir Sigurdsson; Hafdis T Helgadottir; Hrefna Johannsdottir; Olafur T Magnusson; Sigurjon A Gudjonsson; Johanne M Justesen; Marie N Harder; Marit E Jørgensen; Cramer Christensen; Ivan Brandslund; Annelli Sandbæk; Torsten Lauritzen; Henrik Vestergaard; Allan Linneberg; Torben Jørgensen; Torben Hansen; Maryam S Daneshpour; Mohammad-Sadegh Fallah; Astradur B Hreidarsson; Gunnar Sigurdsson; Fereidoun Azizi; Rafn Benediktsson; Gisli Masson; Agnar Helgason; Augustine Kong; Daniel F Gudbjartsson; Oluf Pedersen; Unnur Thorsteinsdottir; Kari Stefansson

doi:10.1038/ng.2882

Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes

Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Patrick Sulem, Hannes Helgason, Niels Grarup, Asgeir Sigurdsson, Hafdis T Helgadottir, Hrefna Johannsdottir, Olafur T Magnusson, Sigurjon A Gudjonsson, Johanne M Justesen, Marie N Harder, Marit E Jørgensen, Cramer Christensen, Ivan Brandslund, Annelli Sandbæk, Torsten Lauritzen, Henrik Vestergaard, Allan Linneberg, Torben JørgensenTorben Hansen, Maryam S Daneshpour, Mohammad-Sadegh Fallah, Astradur B Hreidarsson, Gunnar Sigurdsson, Fereidoun Azizi, Rafn Benediktsson, Gisli Masson, Agnar Helgason, Augustine Kong, Daniel F Gudbjartsson, Oluf Pedersen, Unnur Thorsteinsdottir, Kari Stefansson

190 Citations (Scopus)

Abstract

Through whole-genome sequencing of 2,630 Icelanders and imputation into 11,114 Icelandic cases and 267,140 controls followed by testing in Danish and Iranian samples, we discovered 4 previously unreported variants affecting risk of type 2 diabetes (T2D). A low-frequency (1.47%) variant in intron 1 of CCND2, rs76895963[G], reduces risk of T2D by half (odds ratio (OR) = 0.53, P = 5.0 × 10(-21)) and is correlated with increased CCND2 expression. Notably, this variant is also associated with both greater height and higher body mass index (1.17 cm per allele, P = 5.5 × 10(-12) and 0.56 kg/m(2) per allele, P = 6.5 × 10(-7), respectively). In addition, two missense variants in PAM, encoding p.Asp563Gly (frequency of 4.98%) and p.Ser539Trp (frequency of 0.65%), confer moderately higher risk of T2D (OR = 1.23, P = 3.9 × 10(-10) and OR = 1.47, P = 1.7 × 10(-5), respectively), and a rare (0.20%) frameshift variant in PDX1, encoding p.Gly218Alafs*12, associates with high risk of T2D (OR = 2.27, P = 7.3 × 10(-7)).

Original language	English
Journal	Nature Genetics
Volume	46
Issue number	3
Pages (from-to)	294-300
Number of pages	7
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.2882
Publication status	Published - Mar 2014

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Steinthorsdottir, V., Thorleifsson, G., Sulem, P., Helgason, H., Grarup, N., Sigurdsson, A., Helgadottir, H. T., Johannsdottir, H., Magnusson, O. T., Gudjonsson, S. A., Justesen, J. M., Harder, M. N., Jørgensen, M. E., Christensen, C., Brandslund, I., Sandbæk, A., Lauritzen, T., Vestergaard, H., Linneberg, A., ... Stefansson, K. (2014). Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. Nature Genetics, 46(3), 294-300. https://doi.org/10.1038/ng.2882

Steinthorsdottir, V, Thorleifsson, G, Sulem, P, Helgason, H, Grarup, N, Sigurdsson, A, Helgadottir, HT, Johannsdottir, H, Magnusson, OT, Gudjonsson, SA, Justesen, JM, Harder, MN, Jørgensen, ME, Christensen, C, Brandslund, I, Sandbæk, A, Lauritzen, T, Vestergaard, H , Linneberg, A, Jørgensen, T, Hansen, T, Daneshpour, MS, Fallah, M-S, Hreidarsson, AB, Sigurdsson, G, Azizi, F, Benediktsson, R, Masson, G, Helgason, A, Kong, A, Gudbjartsson, DF, Pedersen, O, Thorsteinsdottir, U & Stefansson, K 2014, 'Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes', Nature Genetics, vol. 46, no. 3, pp. 294-300. https://doi.org/10.1038/ng.2882

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title = "Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes",

abstract = "Through whole-genome sequencing of 2,630 Icelanders and imputation into 11,114 Icelandic cases and 267,140 controls followed by testing in Danish and Iranian samples, we discovered 4 previously unreported variants affecting risk of type 2 diabetes (T2D). A low-frequency (1.47%) variant in intron 1 of CCND2, rs76895963[G], reduces risk of T2D by half (odds ratio (OR) = 0.53, P = 5.0 × 10(-21)) and is correlated with increased CCND2 expression. Notably, this variant is also associated with both greater height and higher body mass index (1.17 cm per allele, P = 5.5 × 10(-12) and 0.56 kg/m(2) per allele, P = 6.5 × 10(-7), respectively). In addition, two missense variants in PAM, encoding p.Asp563Gly (frequency of 4.98%) and p.Ser539Trp (frequency of 0.65%), confer moderately higher risk of T2D (OR = 1.23, P = 3.9 × 10(-10) and OR = 1.47, P = 1.7 × 10(-5), respectively), and a rare (0.20%) frameshift variant in PDX1, encoding p.Gly218Alafs*12, associates with high risk of T2D (OR = 2.27, P = 7.3 × 10(-7)).",

author = "Valgerdur Steinthorsdottir and Gudmar Thorleifsson and Patrick Sulem and Hannes Helgason and Niels Grarup and Asgeir Sigurdsson and Helgadottir, {Hafdis T} and Hrefna Johannsdottir and Magnusson, {Olafur T} and Gudjonsson, {Sigurjon A} and Justesen, {Johanne M} and Harder, {Marie N} and J{\o}rgensen, {Marit E} and Cramer Christensen and Ivan Brandslund and Annelli Sandb{\ae}k and Torsten Lauritzen and Henrik Vestergaard and Allan Linneberg and Torben J{\o}rgensen and Torben Hansen and Daneshpour, {Maryam S} and Mohammad-Sadegh Fallah and Hreidarsson, {Astradur B} and Gunnar Sigurdsson and Fereidoun Azizi and Rafn Benediktsson and Gisli Masson and Agnar Helgason and Augustine Kong and Gudbjartsson, {Daniel F} and Oluf Pedersen and Unnur Thorsteinsdottir and Kari Stefansson",

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doi = "10.1038/ng.2882",

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T1 - Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes

AU - Steinthorsdottir, Valgerdur

AU - Thorleifsson, Gudmar

AU - Sulem, Patrick

AU - Helgason, Hannes

AU - Grarup, Niels

AU - Sigurdsson, Asgeir

AU - Helgadottir, Hafdis T

AU - Johannsdottir, Hrefna

AU - Magnusson, Olafur T

AU - Gudjonsson, Sigurjon A

AU - Justesen, Johanne M

AU - Harder, Marie N

AU - Jørgensen, Marit E

AU - Christensen, Cramer

AU - Brandslund, Ivan

AU - Sandbæk, Annelli

AU - Lauritzen, Torsten

AU - Vestergaard, Henrik

AU - Linneberg, Allan

AU - Jørgensen, Torben

AU - Hansen, Torben

AU - Daneshpour, Maryam S

AU - Fallah, Mohammad-Sadegh

AU - Hreidarsson, Astradur B

AU - Sigurdsson, Gunnar

AU - Azizi, Fereidoun

AU - Benediktsson, Rafn

AU - Masson, Gisli

AU - Helgason, Agnar

AU - Kong, Augustine

AU - Gudbjartsson, Daniel F

AU - Pedersen, Oluf

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

PY - 2014/3

Y1 - 2014/3

N2 - Through whole-genome sequencing of 2,630 Icelanders and imputation into 11,114 Icelandic cases and 267,140 controls followed by testing in Danish and Iranian samples, we discovered 4 previously unreported variants affecting risk of type 2 diabetes (T2D). A low-frequency (1.47%) variant in intron 1 of CCND2, rs76895963[G], reduces risk of T2D by half (odds ratio (OR) = 0.53, P = 5.0 × 10(-21)) and is correlated with increased CCND2 expression. Notably, this variant is also associated with both greater height and higher body mass index (1.17 cm per allele, P = 5.5 × 10(-12) and 0.56 kg/m(2) per allele, P = 6.5 × 10(-7), respectively). In addition, two missense variants in PAM, encoding p.Asp563Gly (frequency of 4.98%) and p.Ser539Trp (frequency of 0.65%), confer moderately higher risk of T2D (OR = 1.23, P = 3.9 × 10(-10) and OR = 1.47, P = 1.7 × 10(-5), respectively), and a rare (0.20%) frameshift variant in PDX1, encoding p.Gly218Alafs*12, associates with high risk of T2D (OR = 2.27, P = 7.3 × 10(-7)).

AB - Through whole-genome sequencing of 2,630 Icelanders and imputation into 11,114 Icelandic cases and 267,140 controls followed by testing in Danish and Iranian samples, we discovered 4 previously unreported variants affecting risk of type 2 diabetes (T2D). A low-frequency (1.47%) variant in intron 1 of CCND2, rs76895963[G], reduces risk of T2D by half (odds ratio (OR) = 0.53, P = 5.0 × 10(-21)) and is correlated with increased CCND2 expression. Notably, this variant is also associated with both greater height and higher body mass index (1.17 cm per allele, P = 5.5 × 10(-12) and 0.56 kg/m(2) per allele, P = 6.5 × 10(-7), respectively). In addition, two missense variants in PAM, encoding p.Asp563Gly (frequency of 4.98%) and p.Ser539Trp (frequency of 0.65%), confer moderately higher risk of T2D (OR = 1.23, P = 3.9 × 10(-10) and OR = 1.47, P = 1.7 × 10(-5), respectively), and a rare (0.20%) frameshift variant in PDX1, encoding p.Gly218Alafs*12, associates with high risk of T2D (OR = 2.27, P = 7.3 × 10(-7)).

U2 - 10.1038/ng.2882

DO - 10.1038/ng.2882

M3 - Journal article

C2 - 24464100

SN - 1061-4036

VL - 46

SP - 294

EP - 300

JO - Nature: New biology

JF - Nature: New biology

IS - 3

ER -

Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes

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