First Genome-Wide Association Study in an Australian Aboriginal Population Provides Insights into Genetic Risk Factors for Body Mass Index and Type 2 Diabetes

被引：29

作者：

Anderson, Denise ^{[1
]}

Cordell, Heather J. ^{[2
]}

Fakiola, Michaela ^{[1
,3
,4
]}

Francis, Richard W. ^{[1
]}

Syn, Genevieve ^{[1
]}

Scaman, Elizabeth S. H. ^{[1
]}

Davis, Elizabeth ^{[1
,5
]}

Miles, Simon J. ^{[6
]}

McLeay, Toby ^{[6
]}

Jamieson, Sarra E. ^{[1
]}

Blackwell, Jenefer M. ^{[1
,3
,4
]}

机构：

[1] Univ Western Australia, Telethon Kids Inst, Subiaco, WA 6008, Australia

[2] Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England

[3] Univ Cambridge, Cambridge Inst Med Res, Dept Med, Cambridge, England

[4] Univ Cambridge, Dept Pathol, Cambridge, England

[5] Princess Margaret Hosp Children, Dept Endocrinol & Diabet, Subiaco, WA 6008, Australia

[6] Ngangganawili Aboriginal Hlth Serv, Wiluna, WA 6646, Australia

来源：

PLOS ONE | 2015年 / 10卷 / 03期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

HEALTH SIGNIFICANT PROGRESS; BETA-CELL FUNCTION; COMMON VARIANTS; GENOTYPE IMPUTATION; SUSCEPTIBILITY GENES; WAIST CIRCUMFERENCE; MULTIPLE ALIGNMENT; METABOLIC SYNDROME; LOCI; TRAITS;

D O I：

10.1371/journal.pone.0119333

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：

A body mass index (BMI) >22kg/m(2) is a risk factor for type 2 diabetes (T2D) in Aboriginal Australians. To identify loci associated with BMI and T2D we undertook a genome-wide association study using 1,075,436 quality-controlled single nucleotide polymorphisms (SNPs) genotyped (Illumina 2.5M Duo Beadchip) in 402 individuals in extended pedigrees from a Western Australian Aboriginal community. Imputation using the thousand genomes (1000G) reference panel extended the analysis to 6,724,284 post quality-control autosomal SNPs. No associations achieved genome-wide significance, commonly accepted as P<5x10(-8). Nevertheless, genes/pathways in common with other ethnicities were identified despite the arrival of Aboriginal people in Australia >45,000 years ago. The top hit (rs10868204 P-genotyped = 1.50x10(-6); rs11140653 P-imputed_1000G = 2.90x10(-7)) for BMI lies 5' of NTRK2, the type 2 neurotrophic tyrosine kinase receptor for brain-derived neurotrophic factor (BDNF) that regulates energy balance downstream of melanocortin-4 receptor (MC4R). PIK3C2G (rs12816270 P-genotyped = 8.06x10(-6); rs10841048 P-imputed_1000G = 6.28x10(-7)) was associated with BMI, but not with T2D as reported elsewhere. BMI also associated with CNTNAP2 (rs6960319 P-genotyped = 4.65x10(-5); rs13225016 P-imputed_1000G = 6.57x10(-5)), previously identified as the strongest gene-by-environment interaction for BMI in African-Americans. The top hit (rs11240074 P-genotyped = 5.59x10-6, P-imputed_1000G = 5.73x10(-6)) for T2D lies 5' of BCL9 that, along with TCF7L2, promotes beta-catenin's transcriptional activity in the WNT signaling pathway. Additional hits occurred in genes affecting pancreatic (KCNJ6, KCNA1) and/or GABA (GABRR1, KCNA1) functions. Notable associations observed for genes previously identified at genome-wide significance in other populations included MC4R (P-genotyped = 4.49x10(-4)) for BMI and IGF2BP2 P-imputed_1000G = 2.55x10(-6)) for T2D. Our results may provide novel functional leads in understanding disease pathogenesis in this Australian Aboriginal population.

引用

页数：25

共 106 条

[1] A general test of association for quantitative traits in nuclear families [J].

Abecasis, GR ;

Cardon, LR ;

Cookson, WOC .

AMERICAN JOURNAL OF HUMAN GENETICS, 2000, 66 (01) :279-292

[2] A Genome-Wide Search for Type 2 Diabetes Susceptibility Genes in an Extended Arab Family [J].

Al Safar, Habiba S. ;

Cordell, Heather J. ;

Jafer, Osman ;

Anderson, Denise ;

Jamieson, Sarra E. ;

Fakiola, Michaela ;

Khazanehdari, Kamal ;

Tay, Guan K. ;

Blackwell, Jenefer M. .

ANNALS OF HUMAN GENETICS, 2013, 77 :488-503

[3]

Alberti KGMM, 1998, DIABETIC MED, V15, P539, DOI 10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO

[4]

2-S

[5] Weak or no association of TCF7L2 variants with Type 2 diabetes risk in an Arab population [J].

Alsmadi, Osama ;

Al-Rubeaan, Khalid ;

Mohamed, Gamal ;

Alkayal, Fadi ;

Al-Saud, Haya ;

Abu Al-Saud, Nouran ;

Al-Daghri, Nasser ;

Mohammad, Shahinaz ;

Meyer, Brian F. .

BMC MEDICAL GENETICS, 2008, 9

[6] An integrated map of genetic variation from 1,092 human genomes [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Schmidt, Jeanette P. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Dinh, Huyen ;

Kovar, Christie ;

Lee, Sandra ;

Lewis, Lora ;

Muzny, Donna ;

Reid, Jeff ;

Wang, Min ;

Wang, Jun ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Li, Zhuo ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Su, Zhe ;

Tai, Shuaishuai ;

Tang, Meifang .

NATURE, 2012, 491 (7422) :56-65

[7] GenABEL: an R library for genome-wide association analysis [J].

Aulchenko, Yurii S. ;

Ripke, Stephan ;

Isaacs, Aaron ;

Van Duijn, Cornelia M. .

BIOINFORMATICS, 2007, 23 (10) :1294-1296

[8] Fast and sensitive multiple alignment of large genomic sequences -: art. no. 66 [J].

Brudno, M ;

Chapman, M ;

Göttgens, B ;

Batzoglou, S ;

Morgenstern, B .

BMC BIOINFORMATICS, 2003, 4 (1)

[9] LAGAN and Multi-LAGAN: Efficient tools for large-scale multiple alignment of genomic DNA [J].

Brudno, M ;

Do, CB ;

Cooper, GM ;

Kim, MF ;

Davydov, E ;

Green, ED ;

Sidow, A ;

Batzoglou, S .

GENOME RESEARCH, 2003, 13 (04) :721-731

[10] The juxtaparanodal proteins CNTNAP2 and TAG1 regulate diet-induced obesity [J].

Buchner, David A. ;

Geisinger, Jon M. ;

Glazebrook, Patricia A. ;

Morgan, Michael G. ;

Spiezio, Sabrina H. ;

Kaiyala, Karl J. ;

Schwartz, Michael W. ;

Sakurai, Takeshi ;

Furley, Andrew J. ;

Kunze, Diana L. ;

Croniger, Colleen M. ;

Nadeau, Joseph H. .

MAMMALIAN GENOME, 2012, 23 (7-8) :431-442

← 1 2 3 4 5 6 7 8 9 10 →