Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes

被引：111

作者：

Flannick, Jason ^{[1
,2
,3
]}

Beer, Nicola L. ^{[1
]}

Bick, Alexander G. ^{[1
,4
]}

Agarwala, Vineeta ^{[1
,5
,6
]}

Molnes, Janne ^{[7
]}

Gupta, Namrata ^{[1
]}

Burtt, Noel P. ^{[1
]}

Florez, Jose C. ^{[1
,8
,9
]}

Meigs, James B. ^{[9
,10
]}

Taylor, Herman ^{[11
,12
,13
]}

Lyssenko, Valeriya ^{[14
]}

Irgens, Henrik ^{[7
,15
]}

Fox, Ervin ^{[11
]}

Burslem, Frank ^{[16
]}

Johansson, Stefan ^{[7
,17
]}

Brosnan, M. Julia ^{[18
]}

Trimmer, Jeff K. ^{[18
]}

Newton-Cheh, Christopher ^{[1
,8
,19
,20
]}

Tuomi, Tiinamaija ^{[21
,22
,23
]}

Molven, Anders ^{[7
,24
,25
]}

Wilson, James G. ^{[26
]}

O'Donnell, Christopher J. ^{[19
,20
,27
]}

Kathiresan, Sekar ^{[1
,8
,20
]}

Hirschhorn, Joel N. ^{[1
,4
,28
,29
,30
]}

Njolstad, Pal R. ^{[1
,7
,15
]}

Rolph, Tim ^{[18
]}

Seidman, J. G. ^{[4
]}

Gabriel, Stacey ^{[1
]}

Cox, David R. ^{[31
]}

Seidman, Christine E. ^{[4
,32
,33
]}

Groop, Leif ^{[14
,34
]}

Altshuler, David ^{[1
,2
,4
,9
]}

机构：

[1] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA

[2] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[3] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA

[4] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[5] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA

[6] Harvard Univ, Grad Sch Arts & Sci, Program Biophys, Cambridge, MA 02138 USA

[7] Univ Bergen, KG Jebsen Ctr Diabet Res, Dept Clin Sci, Bergen, Norway

[8] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[9] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[10] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA

[11] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA

[12] Jackson State Univ, Jackson, MS USA

[13] Tougaloo Coll, Div Nat Sci, Tougaloo, MS USA

[14] Lund Univ, Clin Res Ctr, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden

[15] Haukeland Hosp, Dept Pediat, N-5021 Bergen, Norway

[16] Prescient Life Sci, Cardiovasc & Metab Dis Practice, London, England

[17] Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway

[18] Pfizer Inc, Cardiovasc & Metab Dis Res Unit, Cambridge, MA USA

[19] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA

[20] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA

[21] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland

[22] Univ Helsinki, Cent Hosp, Dept Med, Helsinki, Finland

[23] Univ Helsinki, Cent Hosp, Res Program Mol Med, Helsinki, Finland

[24] Univ Bergen, Dept Clin Med, Gade Lab Pathol, Bergen, Norway

[25] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway

[26] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA

[27] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA

[28] Childrens Hosp, Div Genet, Boston, MA 02115 USA

[29] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[30] Childrens Hosp, Program Genom, Boston, MA 02115 USA

[31] Pfizer Inc, Appl Quantitat Genotherapeut, San Francisco, CA USA

[32] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA

[33] Howard Hughes Med Inst, Chevy Chase, MD USA

[34] Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland

来源：

NATURE GENETICS | 2013年 / 45卷 / 11期

基金：

欧洲研究理事会; 美国国家卫生研究院;

关键词：

FACTOR-I; NUCLEAR FACTOR-1-ALPHA; READ ALIGNMENT; ALPHA-GENE; ONSET; MUTATIONS; YOUNG; INSULIN; GLUCOKINASE; MODY;

D O I：

10.1038/ng.2794

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders1-7 and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates8-12. We sequenced seven genes for maturity-onset diabetes of the young (MODY) 13 in well-phenotyped population samples14,15 (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases.

引用

页码：1380 / +

页数：8

共 92 条

[1] MAPPING OF THE GENE-TCF2 CODING FOR THE TRANSCRIPTION FACTOR LFB3 TO HUMAN CHROMOSOME-17 BY POLYMERASE CHAIN-REACTION [J].

ABBOTT, C ;

PIAGGIO, G ;

AMMENDOLA, R ;

SOLOMON, E ;

POVEY, S ;

GOUNARI, F ;

DESIMONE, V ;

CORTESE, R .

GENOMICS, 1990, 8 (01) :165-167

[2] A method and server for predicting damaging missense mutations [J].

Adzhubei, Ivan A. ;

Schmidt, Steffen ;

Peshkin, Leonid ;

Ramensky, Vasily E. ;

Gerasimova, Anna ;

Bork, Peer ;

Kondrashov, Alexey S. ;

Sunyaev, Shamil R. .

NATURE METHODS, 2010, 7 (04) :248-249

[3] GATA6 haploinsufficiency causes pancreatic agenesis in humans [J].

Allen, Hana Lango ;

Flanagan, Sarah E. ;

Shaw-Smith, Charles ;

De Franco, Elisa ;

Akerman, Ildem ;

Caswell, Richard ;

Ferrer, Jorge ;

Hattersley, Andrew T. ;

Ellard, Sian .

NATURE GENETICS, 2012, 44 (01) :20-22

[4] A map of human genome variation from population-scale sequencing [J].

Altshuler, David ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Collins, Francis S. ;

De la Vega, Francisco M. ;

Donnelly, Peter ;

Egholm, Michael ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Knoppers, Bartha M. ;

Lander, Eric S. ;

Lehrach, Hans ;

Mardis, Elaine R. ;

McVean, Gil A. ;

Nickerson, DebbieA. ;

Peltonen, Leena ;

Schafer, Alan J. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Deiros, David ;

Metzker, Mike ;

Muzny, Donna ;

Reid, Jeff ;

Wheeler, David ;

Wang, Jun ;

Li, Jingxiang ;

Jian, Min ;

Li, Guoqing ;

Li, Ruiqiang ;

Liang, Huiqing ;

Tian, Geng ;

Wang, Bo ;

Wang, Jian ;

Wang, Wei ;

Yang, Huanming ;

Zhang, Xiuqing ;

Zheng, Huisong ;

Lander, Eric S. ;

Altshuler, David L. ;

Ambrogio, Lauren ;

Bloom, Toby ;

Cibulskis, Kristian ;

Fennell, Tim J. ;

Gabriel, Stacey B. .

NATURE, 2010, 467 (7319) :1061-1073

[5]

[Anonymous], DIABET MED

[6]

[Anonymous], 2009, NEW YORK TIMES 0607

[7]

[Anonymous], NY TIMES

[8]

[Anonymous], AM J PUBLIC HEALTH

[9]

[Anonymous], GUARDIAN

[10]

[Anonymous], 2006, Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia: Report of a WHO/IDF consultation

← 1 2 3 4 5 6 7 8 9 10 →