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

被引：224

作者：

Steinthorsdottir, Valgerdur ^{[1
]}

Thorleifsson, Gudmar ^{[1
]}

Sulem, Patrick ^{[1
]}

Helgason, Hannes ^{[1
,2
]}

Grarup, Niels ^{[3
]}

Sigurdsson, Asgeir ^{[1
]}

Helgadottir, Hafdis T. ^{[1
]}

Johannsdottir, Hrefna ^{[1
]}

Magnusson, Olafur T. ^{[1
]}

Gudjonsson, Sigurjon A. ^{[1
]}

Justesen, Johanne M. ^{[3
]}

Harder, Marie N. ^{[3
]}

Jorgensen, Marit E. ^{[4
]}

Christensen, Cramer ^{[5
]}

Brandslund, Ivan ^{[6
,7
]}

Sandbaek, Annelli ^{[8
]}

Lauritzen, Torsten ^{[8
]}

Vestergaard, Henrik ^{[3
]}

Linneberg, Allan ^{[9
]}

Jorgensen, Torben ^{[9
,10
,11
]}

Hansen, Torben ^{[3
]}

Daneshpour, Maryam S. ^{[12
]}

Fallah, Mohammad-Sadegh ^{[12
]}

Hreidarsson, Astradur B. ^{[13
]}

Sigurdsson, Gunnar ^{[13
]}

Azizi, Fereidoun ^{[14
]}

Benediktsson, Rafn ^{[13
]}

Masson, Gisli ^{[1
]}

Helgason, Agnar ^{[1
,15
]}

Kong, Augustine ^{[1
,2
]}

Gudbjartsson, Daniel F. ^{[1
,2
]}

Pedersen, Oluf ^{[3
]}

Thorsteinsdottir, Unnur ^{[1
,16
]}

Stefansson, Kari ^{[1
,16
]}

机构：

[1] deCODE Genet Amgen Inc, Reykjavik, Iceland

[2] Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland

[3] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark

[4] Steno Diabet Ctr, DK-2820 Gentofte, Denmark

[5] Vejle Hosp, Dept Internal Med & Endocrinol, Vejle, Denmark

[6] Vejle Hosp, Dept Clin Biochem, Vejle, Denmark

[7] Univ Southern Denmark, Inst Reg Hlth Res, Odense, Denmark

[8] Univ Aarhus, Sect Gen Practice, Dept Publ Hlth, Aarhus, Denmark

[9] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark

[10] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark

[11] Aalborg Univ, Fac Med, Aalborg, Denmark

[12] Shahid Beheshti Univ Med Sci, Cellular & Mol Endocrine Res Ctr, Res Inst Endocrine Sci, Tehran, Iran

[13] Natl Univ Hosp Iceland, Dept Endocrinol & Metab, Landspitali, Reykjavik, Iceland

[14] Shahid Beheshti Univ Med Sci, Res Inst Endocrine Sci, Endocrine Res Ctr, Tehran, Iran

[15] Univ Iceland, Dept Anthropol, Reykjavik, Iceland

[16] Univ Iceland, Fac Med, Reykjavik, Iceland

来源：

NATURE GENETICS | 2014年 / 46卷 / 03期

关键词：

GENE; MORBIDITY; MUTATION;

D O I：

10.1038/ng.2882

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 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 x 10(-12) and 0.56 kg/m(2) per allele, P = 6.5 x 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 x 10(-10) and OR = 1.47, P = 1.7 x 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 x 10(-7)).

引用

页码：294 / +

页数：7

共 30 条

[1] Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes
Albrechtsen, A.
Grarup, N.
Li, Y.
Sparso, 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.
Stancakova, 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.
[J]. DIABETOLOGIA, 2013, 56 (02) : 298 - 310
[2] Prevention of non-communicable disease in a population in nutrition transition: Tehran Lipid and Glucose Study phase II
Azizi, Fereidoun
Ghanbarian, Arash
Momenan, Amir Abbas
Hadaegh, Farzad
Mirmiran, Parvin
Hedayati, Mehdi
Mehrabi, Yadollah
Zahedi-Asl, Saleh
[J]. TRIALS, 2009, 10
[3] Deletion of peptide amidation enzymatic activity leads to edema and embryonic lethality in the mouse
Czyzyk, TA
Ning, Y
Hsu, MS
Peng, B
Mains, RE
Eipper, BA
Pintar, JE
[J]. DEVELOPMENTAL BIOLOGY, 2005, 287 (02) : 301 - 313
[4] Sequencing PDX1 (insulin promoter factor 1) in 1788 UK individuals found 5% had a low frequency coding variant, but these variants are not associated with Type 2 diabetes
Edghill, E. L.
Khamis, A.
Weedon, M. N.
Walker, M.
Hitman, G. A.
McCarthy, M. I.
Owen, K. R.
Ellard, S.
Hattersley, A. T.
Frayling, T. M.
[J]. DIABETIC MEDICINE, 2011, 28 (06) : 681 - 684
[5] THE BIOSYNTHESIS OF NEUROPEPTIDES - PEPTIDE ALPHA-AMIDATION
EIPPER, BA
STOFFERS, DA
MAINS, RE
[J]. ANNUAL REVIEW OF NEUROSCIENCE, 1992, 15 : 57 - 85
[6] Genetics of gene expression and its effect on disease
Emilsson, Valur
Thorleifsson, Gudmar
Zhang, Bin
Leonardson, Amy S.
Zink, Florian
Zhu, Jun
Carlson, Sonia
Helgason, Agnar
Walters, G. Bragi
Gunnarsdottir, Steinunn
Mouy, Magali
Steinthorsdottir, Valgerdur
Eiriksdottir, Gudrun H.
Bjornsdottir, Gyda
Reynisdottir, Inga
Gudbjartsson, Daniel
Helgadottir, Anna
Jonasdottir, Aslaug
Jonasdottir, Adalbjorg
Styrkarsdottir, Unnur
Gretarsdottir, Solveig
Magnusson, Kristinn P.
Stefansson, Hreinn
Fossdal, Ragnheidur
Kristjansson, Kristleifur
Gislason, Hjortur G.
Stefansson, Tryggvi
Leifsson, Bjorn G.
Thorsteinsdottir, Unnur
Lamb, John R.
Gulcher, Jeffrey R.
Reitman, Marc L.
Kong, Augustine
Schadt, Eric E.
Stefansson, Kari
[J]. NATURE, 2008, 452 (7186) : 423 - U2
[7] β cell replication is the primary mechanism for maintaining postnatal β cell mass
Georgia, S
Bhushan, A
[J]. JOURNAL OF CLINICAL INVESTIGATION, 2004, 114 (07) : 963 - 968
[8] The gene encoding phosphodiesterase 4D confers risk of ischemic stroke
Gretarsdottir, S
Thorleifsson, G
Reynisdottir, ST
Manolescu, A
Jonsdottir, S
Jonsdottir, T
Gudmundsdottir, T
Bjarnadottir, SM
Einarsson, OB
Gudjonsdottir, HM
Hawkins, M
Gudmundsson, G
Gudmundsdottir, H
Andrason, H
Gudmundsdottir, AS
Sigurdardottir, M
Chou, TT
Nahmias, J
Goss, S
Sveinbjörnsdottir, S
Valdimarsson, EM
Jakobsson, F
Agnarsson, U
Gudnason, V
Thorgeirsson, G
Fingerle, J
Gurney, M
Gudbjartsson, D
Frigge, ML
Kong, A
Stefansson, K
Gulcher, JR
[J]. NATURE GENETICS, 2003, 35 (02) : 131 - 138
[9] Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution
Helgason, Agnar
Palsson, Snaebjorn
Thorleifsson, Gudmar
Grant, Struan F. A.
Emilsson, Valur
Gunnarsdottir, Steinunn
Adeyemo, Adebowale
Chen, Yuanxiu
Chen, Guanjie
Reynisdottir, Inga
Benediktsson, Rafn
Hinney, Anke
Hansen, Torben
Andersen, Gitte
Borch-Johnsen, Knut
Jorgensen, Torben
Schaefer, Helmut
Faruque, Mezbah
Doumatey, Ayo
Zhou, Jie
Wilensky, Robert L.
Reilly, Muredach P.
Rader, Daniel J.
Bagger, Yu
Christiansen, Claus
Sigurdsson, Gunnar
Hebebrand, Johannes
Pedersen, Oluf
Thorsteinsdottir, Unnur
Gulcher, Jeffrey R.
Kong, Augustine
Rotimi, Charles
Stefansson, Kari
[J]. NATURE GENETICS, 2007, 39 (02) : 218 - 225
[10] Hindorff L., CATALOG PUBLISHED GE

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