Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

被引：338

作者：

Jacquemont, Sebastien ^{[1
]}

Reymond, Alexandre ^{[2
]}

Zufferey, Flore ^{[1
]}

Harewood, Louise ^{[2
]}

Walters, Robin G. ^{[3
]}

Kutalik, Zoltan ^{[4
,5
]}

Martinet, Danielle ^{[1
]}

Shen, Yiping ^{[6
,7
]}

Valsesia, Armand ^{[4
,5
,8
]}

Beckmann, Noam D. ^{[1
]}

Thorleifsson, Gudmar ^{[9
]}

Belfiore, Marco ^{[1
]}

Bouquillon, Sonia ^{[10
]}

Campion, Dominique ^{[11
,12
]}

de Leeuw, Nicole ^{[13
,14
]}

de Vries, Bert B. A. ^{[13
,14
]}

Esko, Tonu ^{[15
,16
]}

Fernandez, Bridget A. ^{[17
]}

Fernandez-Aranda, Fernando ^{[18
]}

Manuel Fernandez-Real, Jose ^{[19
]}

Gratacos, Monica ^{[20
]}

Guilmatre, Audrey ^{[11
,12
]}

Hoyer, Juliane ^{[21
]}

Jarvelin, Marjo-Riitta ^{[22
,23
,24
,25
]}

Kooy, R. Frank ^{[26
,27
]}

Kurg, Ants ^{[15
]}

Le Caignec, Cedric ^{[28
]}

Maennik, Katrin ^{[15
]}

Platt, Orah S. ^{[6
]}

Sanlaville, Damien ^{[29
,30
]}

Van Haelst, Mieke M. ^{[3
,31
]}

Villatoro Gomez, Sergi ^{[20
]}

Walha, Faida ^{[2
]}

Wu, Bai-lin ^{[6
,32
,33
]}

Yu, Yongguo ^{[6
,34
]}

Aboura, Azzedine ^{[35
]}

Addor, Marie-Claude ^{[1
]}

Alembik, Yves ^{[36
]}

Antonarakis, Stylianos E. ^{[37
]}

Arveiler, Benoit ^{[38
,39
]}

Barth, Magalie ^{[40
]}

Bednarek, Nathalie ^{[41
]}

Bena, Frederique ^{[37
]}

Bergmann, Sven ^{[4
,5
]}

Beri, Mylene ^{[42
]}

Bernardini, Laura ^{[43
]}

Blaumeiser, Bettina ^{[26
,27
]}

Bonneau, Dominique ^{[40
]}

Bottani, Armand ^{[37
]}

Boute, Odile ^{[44
]}

机构：

[1] CHU Vaudois, Serv Med Genet, CH-1011 Lausanne, Switzerland

[2] Univ Lausanne, Ctr Integrat Genom, CH-1015 Lausanne, Switzerland

[3] Univ London Imperial Coll Sci Technol & Med, Dept Genom Common Dis, London W12 0NN, England

[4] Univ Lausanne, Dept Med Genet, CH-1005 Lausanne, Switzerland

[5] Univ Lausanne, Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland

[6] Childrens Hosp Boston, Boston, MA 02115 USA

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

[8] Univ Lausanne, Ludwig Inst Canc Res, CH-1015 Lausanne, Switzerland

[9] deCODE Genet, IS-101 Reykjavik, Iceland

[10] CHRU Lille, Hop Jeanne de Flandre, Med Genet Lab, F-59000 Lille, France

[11] Univ Rouen, INSERM U614, F-76000 Rouen, France

[12] Ctr Hosp Rouvray, F-76000 Rouen, France

[13] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen Ctr Mol Life Sci, NL-6500 HB Nijmegen, Netherlands

[14] Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Disorders, NL-6500 HB Nijmegen, Netherlands

[15] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia

[16] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia

[17] Mem Univ Newfoundland, Discipline Genet & Med, St John, NF A1B 3V6, Canada

[18] Univ Hosp Bellvitge IDIBELL, Ciber Fisiopatol Obesidad & Nutr CIBEROBN, Dept Psychiat, Barcelona 08907, Spain

[19] Hosp Univ Girona Dr Josep Trueta, Dept Diabet Endocrinol & Nutr, Ciber Fisiopatol Obesidad & Nutr CIBEROBN, Inst Invest Biomed Girona,Inst Salud Carlos III, Girona 17007, Spain

[20] CIBER Epidemiol & Salud Publ CIBERESP, Ctr Genom Regulat CRG UPF, Genes & Dis Program, Barcelona 08003, Catalonia, Spain

[21] Univ Erlangen Nurnberg, Inst Human Genet, D-91054 Erlangen, Germany

[22] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1PG, England

[23] Natl Inst Hlth & Welf, Dept Child & Adolescent Hlth, Oulu 90101, Finland

[24] Univ Oulu, Inst Hlth Sci, FIN-90570 Oulu, Finland

[25] 90014 Univ Oulu, Univ Oulu, Bioctr Oulu, Oulu, Finland

[26] Univ Antwerp, Dept Med Genet, B-2650 Antwerp, Belgium

[27] Univ Antwerp Hosp, B-2650 Antwerp, Belgium

[28] CHU Nantes, Serv Genet Med, Nantes, France

[29] CHU Lyon, Hosp Civils Lyon, Serv Cytogenet Constitut, F-69000 Lyon, France

[30] UCBL1, TIGER Team, Neurosci Res Ctr, F-69000 Lyon, France

[31] Univ Med Ctr, Dept Med Genet, NL-3584 EA Utrecht, Netherlands

[32] Fudan Univ, Childrens Hosp, Shanghai 200032, Peoples R China

[33] Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China

[34] Shanghai Childrens Med Ctr, Shanghai 200127, Peoples R China

[35] Robert DEBRE Univ Hosp, APHP, Dept Genet, F-75019 Paris, France

[36] CHU Strasbourg, Hop Hautepierre, Serv Genet Med, F-67000 Strasbourg, France

[37] Univ Hosp Geneva, Serv Genet Med, CH-1205 Geneva, Switzerland

[38] Univ Bordeaux 2, Lab Malad Rares Genet & Metab, F-33076 Bordeaux, France

[39] CHU Bordeaux, Serv Genet Med, F-33076 Bordeaux, France

[40] CHU Angers, Serv Genet, F-49933 Angers, France

[41] CHU Hop Alix de Champagne, Serv Pediat, F-51100 Reims, France

[42] CHU Nancy, Genet Lab, F-54511 Vandoeuvre Les Nancy, France

[43] IRCCS Casa Sollievo della Sofferenza Hosp, Mendel Lab, I-71013 San Giovanni Rotondo, Italy

[44] CHRU Lille, Hop Jeanne de Flandre, Serv Genet Clin, F-59037 Lille, France

[45] CHU Caremeau, Lab Cytogenet, F-30029 Nimes, France

[46] CHU Grenoble, Lab Genet Chromosom, F-38043 Grenoble, France

[47] CHRU Lille, Hop Roger Salengro, Serv Neurol Pediat, F-59037 Lille, France

[48] CHU St Etienne, Serv Genet, CHU Hop Nord, F-42055 St Etienne, France

[49] GHICL, Hop St Vincent de Paul, Ctr Genet Chromosom, F-59160 Lille, France

[50] CHRU Amiens, Serv Genet Med, F-80000 Amiens, France

来源：

NATURE | 2011年 / 478卷 / 7367期

基金：

芬兰科学院; 英国医学研究理事会; 英国惠康基金; 瑞士国家科学基金会;

关键词：

COPY NUMBER VARIATION; BODY-MASS INDEX; DEPENDENT PROBE AMPLIFICATION; CIRCULAR BINARY SEGMENTATION; TIME QUANTITATIVE PCR; HIDDEN-MARKOV MODEL; SNP GENOTYPING DATA; FAILURE-TO-THRIVE; RELATIVE QUANTIFICATION; METABOLIC SYNDROME;

D O I：

10.1038/nature10406

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Both obesity and being underweight have been associated with increased mortality(1,2). Underweight, defined as a body mass index (BMI) <= 18.5 kg per m(2) in adults and <= -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive(3-5), feeding and eating disorder and/or anorexia nervosa(6,7). In contrast to obesity, few genetic variants underlying these clinical conditions have been reported(8,9). We previously showed that hemizygosity of a similar to 600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities(10). Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.

引用

页码：97 / U111

页数：8

共 61 条

[51] Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size [J].

Shinawi, Marwan ;

Liu, Pengfei ;

Kang, Sung-Hae L. ;

Shen, Joseph ;

Belmont, John W. ;

Scott, Daryl A. ;

Probst, Frank J. ;

Craigen, William J. ;

Graham, Brett H. ;

Pursley, Amber ;

Clark, Gary ;

Lee, Jennifer ;

Proud, Monica ;

Stocco, Amber ;

Rodriguez, Diana L. ;

Kozel, Beth A. ;

Sparagana, Steven ;

Roeder, Elizabeth R. ;

McGrew, Susan G. ;

Kurczynski, Thaddeus W. ;

Allison, Leslie J. ;

Amato, Stephen ;

Savage, Sarah ;

Patel, Ankita ;

Stankiewicz, Pawel ;

Beaudet, Arthur L. ;

Cheung, Sau Wai ;

Lupski, James R. .

JOURNAL OF MEDICAL GENETICS, 2010, 47 (05) :332-341

[52] Rapid, high throughput prenatal detection of aneuploidy using a novel quantitative method (MLPA) [J].

Slater, HR ;

Bruno, DL ;

Ren, H ;

Pertile, M ;

Schouten, JP ;

Choo, KHA .

JOURNAL OF MEDICAL GENETICS, 2003, 40 (12) :907-912

[53] Relative impact of nucleotide and copy number variation on gene expression phenotypes [J].

Stranger, Barbara E. ;

Forrest, Matthew S. ;

Dunning, Mark ;

Ingle, Catherine E. ;

Beazley, Claude ;

Thorne, Natalie ;

Redon, Richard ;

Bird, Christine P. ;

de Grassi, Anna ;

Lee, Charles ;

Tyler-Smith, Chris ;

Carter, Nigel ;

Scherer, Stephen W. ;

Tavare, Simon ;

Deloukas, Panagiotis ;

Hurles, Matthew E. ;

Dermitzakis, Emmanouil T. .

SCIENCE, 2007, 315 (5813) :848-853

[54] Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes [J].

Vandesompele, Jo ;

De Preter, Katleen ;

Pattyn, Filip ;

Poppe, Bruce ;

Van Roy, Nadine ;

De Paepe, Anne ;

Speleman, Frank .

GENOME BIOLOGY, 2002, 3 (07)

[55] A faster circular binary segmentation algorithm for the analysis of array CGH data [J].

Venkatraman, E. S. ;

Olshen, Adam B. .

BIOINFORMATICS, 2007, 23 (06) :657-663

[56] A new highly penetrant form of obesity due to deletions on chromosome 16p11.2 [J].

Walters, R. G. ;

Jacquemont, S. ;

Valsesia, A. ;

de Smith, A. J. ;

Martinet, D. ;

Andersson, J. ;

Falchi, M. ;

Chen, F. ;

Andrieux, J. ;

Lobbens, S. ;

Delobel, B. ;

Stutzmann, F. ;

Moustafa, J. S. El-Sayed ;

Chevre, J. -C. ;

Lecoeur, C. ;

Vatin, V. ;

Bouquillon, S. ;

Buxton, J. L. ;

Boute, O. ;

Holder-Espinasse, M. ;

Cuisset, J. -M. ;

Lemaitre, M. -P. ;

Ambresin, A. -E. ;

Brioschi, A. ;

Gaillard, M. ;

Giusti, V. ;

Fellmann, F. ;

Ferrarini, A. ;

Hadjikhani, N. ;

Campion, D. ;

Guilmatre, A. ;

Goldenberg, A. ;

Calmels, N. ;

Mandel, J. -L. ;

Le Caignec, C. ;

David, A. ;

Isidor, B. ;

Cordier, M. -P. ;

Dupuis-Girod, S. ;

Labalme, A. ;

Sanlaville, D. ;

Beri-Dexheimer, M. ;

Jonveaux, P. ;

Leheup, B. ;

Ounap, K. ;

Bochukova, E. G. ;

Henning, E. ;

Keogh, J. ;

Ellis, R. J. ;

MacDermot, K. D. .

NATURE, 2010, 463 (7281) :671-U104

[57] Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response [J].

Wang, Bin ;

Matsuoka, Shuhei ;

Ballif, Bryan A. ;

Zhang, Dong ;

Smogorzewska, Agata ;

Gygi, Steven P. ;

Elledge, Stephen J. .

SCIENCE, 2007, 316 (5828) :1194-1198

[58] A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa [J].

Wang, K. ;

Zhang, H. ;

Bloss, C. S. ;

Duvvuri, V. ;

Kaye, W. ;

Schork, N. J. ;

Berrettini, W. ;

Hakonarson, H. .

MOLECULAR PSYCHIATRY, 2011, 16 (09) :949-959

[59] PennCNV: An integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data [J].

Wang, Kai ;

Li, Mingyao ;

Hadley, Dexter ;

Liu, Rui ;

Glessner, Joseph ;

Grant, Struan F. A. ;

Hakonarson, Hakon ;

Bucan, Maja .

GENOME RESEARCH, 2007, 17 (11) :1665-1674

[60] Association between microdeletion and microduplication at 16p11.2 and autism [J].

Weiss, Lauren A. ;

Shen, Yiping ;

Korn, Joshua M. ;

Arking, Dan E. ;

Miller, David T. ;

Fossdal, Ragnheidur ;

Saemundsen, Evald ;

Stefansson, Hreinn ;

Ferreira, Manuel A. R. ;

Green, Todd ;

Platt, Orah S. ;

Ruderfer, Douglas M. ;

Walsh, Christopher A. ;

Altshuler, David ;

Chakravarti, Aravinda ;

Tanzi, Rudolph E. ;

Stefansson, Kari ;

Santangelo, Susan L. ;

Gusella, James F. ;

Sklar, Pamela ;

Wu, Bai-Lin ;

Daly, Mark J. .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (07) :667-675

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