Transethnic insight into the genetics of glycaemic traits: fine-mapping results from the Population Architecture using Genomics and Epidemiology (PAGE) consortium (Pg 2384, Vol 60, 2017)

被引：0

作者：

Bien, Stephanie A. ^{[1
]}

Pankow, James S. ^{[2
]}

Haesslert, Jeffrey ^{[1
]}

Lu, Yinchang ^{[3
]}

Pankratz, Nathan ^{[4
]}

Rohde, Rebecca R. ^{[5
]}

Tamuno, Alfred ^{[6
]}

Carlson, Christopher S. ^{[1
]}

Schumacher, Fredrick R. ^{[7
]}

Buzkova, Petra ^{[8
]}

Daviglus, Martha L. ^{[9
]}

Lim, Unhee ^{[10
]}

Fornage, Myriam ^{[11
]}

Fernandez-Rhodes, Lindsay ^{[5
]}

Aviles-Santa, Larissa ^{[12
]}

Buyske, Steven ^{[13
,14
]}

Grosso, Myron D.

Graff, Mariaelisa ^{[5
]}

Isasi, Carmen R. ^{[15
]}

Kuller, Lewis H. ^{[16
]}

Manson, JoAnn E. ^{[17
]}

Matise, Tara C. ^{[13
]}

Prentice, Ross L. ^{[1
]}

Wilkens, Lynne R. ^{[10
]}

Yoneyama, Sachiko ^{[18
,19
]}

Loos, Ruth J. E. ^{[6
,20
,21
,22
]}

Hindorff, Lucia A. ^{[23
]}

Le Marchand, Loic ^{[10
]}

North, Kari E. ^{[5
,24
]}

Haiman, Christopher A. ^{[25
]}

Peters, Ulrike ^{[1
]}

Kooperberg, Charles ^{[1
]}

机构：

[1] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N, Seattle, WA 98109 USA

[2] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA

[3] Vanderbilt Univ, Dept Biol Sci, 221 Kirkland Hall, Nashville, TN 37235 USA

[4] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA

[5] Univ North Carolina Chapel Hill, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA

[6] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA

[7] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA

[8] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[9] Univ Illinois, Inst Minor Hlth Res, Dept Med, Chicago, IL USA

[10] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA

[11] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA

[12] NHLBI, NIH, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA

[13] Rutgers State Univ, Dept Genet, Piscataway, NJ USA

[14] Rutgers State Univ, Dept Stat, Newark, NJ USA

[15] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA

[16] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA

[17] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[18] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA

[19] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA

[20] Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England

[21] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[22] Icahn Sch Med Mt Sinai, New York, NY 10029 USA

[23] NHGRI, NIH, Bethesda, MD 20892 USA

[24] Univ North Carolina Chapel Hill, Carolina Ctr Genome Sci, Chapel Hill, NC USA

[25] Univ Southern Calif, Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA

来源：

DIABETOLOGIA | 2017年 / 60卷 / 12期

关键词：

Fine-mapping; Genetic; Glucose; Glycaemic; Insulin; Multiethnic; Page; Transethnic; Type; 2; diabetes;

D O I：

10.1007/s00125-017-4476-z

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aims/hypothesis Elevated levels of fasting glucose and fasting insulin in non-diabetic individuals are markers of dysregulation of glucose metabolism and are strong risk factors for type 2 diabetes. Genome-wide association studies have discovered over 50 SNPs associated with these traits. Most of these loci were discovered in European populations and have not been tested in a well-powered multi-ethnic study. We hypothesised that a large, ancestrally diverse, fine-mapping genetic study of glycaemic traits would identify novel and population-specific associations that were previously undetectable by European-centric studies. Methods A multiethnic study of up to 26,760 unrelated individuals without diabetes, of predominantly Hispanic/Latino and African ancestries, were genotyped using the Metabochip. Transethnic meta-analysis of racial/ethnic-specific linear regression analyses were performed for fasting glucose and fasting insulin. We attempted to replicate 39 fasting glucose and 17 fasting insulin loci. Genetic fine-mapping was performed through sequential conditional analyses in 15 regions that included both the initially reported SNP association(s) and denser coverage of SNP markers. In addition, Metabochip-wide analyses were performed to discover novel fasting glucose and fasting insulin loci. The most significant SNP associations were further examined using bio-informatic functional annotation. Results Previously reported SNP associations were significantly replicated (p <= 0.05) in 31/39 fasting glucose loci and 14/17 fasting insulin loci. Eleven glycaemic trait loci were refined to a smaller list of potentially causal variants through transethnic meta-analysis. Stepwise conditional analysis identified two loci with independent secondary signals (G6PC2-rs477224 and GCK-rs2908290), which had not previously been reported. Population-specific conditional analyses identified an independent signal in G6PC2 tagged by the rare variant rs77719485 in African ancestry. Further Metabochip-wide analysis uncovered one novel fasting insulin locus at SLC17A2-rs75862513. Conclusions/interpretation These findings suggest that while glycaemic trait loci often have generalisable effects across the studied populations, transethnic genetic studies help to prioritise likely functional SNPs, identify novel associations that may be population-specific and in turn have the potential to influence screening efforts or therapeutic discoveries. Data availability The summary statistics from each of the ancestry-specific and transethnic (combined ancestry) results can be found under the PAGE study on dbGaP here: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000356.v1.p1

引用

页码：2542 / 2543

页数：2