Impact of Common Variation in Bone-Related Genes on Type 2 Diabetes and Related Traits

Liana K. Billings; Yi-Hsiang Hsu; Rachel J. Ackerman; Josee Dupuis; Benjamin F. Voight; Laura J. Rasmussen-Torvik; Serge Hercberg; Mark Lathrop; Daniel Barnes; Claudia Langenberg; Jennie Hui; Mao Fu; Nabila Bouatia-Naji; Cecile Lecoeur; Ping An; Patrik K. Magnusson; Ida Surakkaza; Samuli Ripatti; Lene Christiansen; Christine Dalgard; Lasse Folkersen; Elin Grundberg; Per Eriksson; Jaakko Kaprio; Kirsten Ohm Kyvik; Nancy L. Pedersen; Ingrid B. Borecki; Michael A. Province; Beverley Balkau; Philippe Froguel; Alan R. Shuldiner; Lyle J. Palmer; Nick Wareham; Pierre Meneton; Toby Johnson; James S. Pankow; David Karasik; James B. Meigs; Douglas P. Kiel; Jose C. Florez; ASCOT Investigators, DIAGRAM Consortium, MuTHER Consortium, MAGIC Investigators, GEFOS Consortium

doi:10.2337/db11-1515

Impact of Common Variation in Bone-Related Genes on Type 2 Diabetes and Related Traits

Liana K. Billings, Yi-Hsiang Hsu, Rachel J. Ackerman, Josee Dupuis, Benjamin F. Voight, Laura J. Rasmussen-Torvik, Serge Hercberg, Mark Lathrop, Daniel Barnes, Claudia Langenberg, Jennie Hui, Mao Fu, Nabila Bouatia-Naji, Cecile Lecoeur, Ping An, Patrik K. Magnusson, Ida Surakkaza, Samuli Ripatti, Lene Christiansen, Christine DalgardLasse Folkersen, Elin Grundberg, Per Eriksson, Jaakko Kaprio, Kirsten Ohm Kyvik, Nancy L. Pedersen, Ingrid B. Borecki, Michael A. Province, Beverley Balkau, Philippe Froguel, Alan R. Shuldiner, Lyle J. Palmer, Nick Wareham, Pierre Meneton, Toby Johnson, James S. Pankow, David Karasik, James B. Meigs, Douglas P. Kiel, Jose C. Florez, ASCOT Investigators, DIAGRAM Consortium, MuTHER Consortium, MAGIC Investigators, GEFOS Consortium

Twin Research & Genetic Epidemiology

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28 Citations (Scopus)

Abstract

Exploring genetic pleiotropy can provide clues to a mechanism underlying the observed epidemiological association between type 2 diabetes and heightened fracture risk. We examined genetic variants associated with bone mineral density (BMD) for association with type 2 diabetes and glycemic traits in large well-phenotyped and -genotyped consortia. We undertook follow-up analysis in similar to 19,000 individuals and assessed gene expression. We queried single nucleotide polymorphisms (SNPs) associated with BMD at levels of genome-wide significance, variants in linkage disequilibrium (r(2) > 0.5), and BMD candidate genes. SNP rs6867040, at the ITGA1 locus, was associated with a 0.0166 mmol/L (0.004) increase in fasting glucose per C allele in the combined analysis. Genetic variants in the ITGA1 locus were associated with its expression in the liver but not in adipose tissue. ITGA1 variants appeared among the top loci associated with type 2 diabetes, fasting insulin, beta-cell function by homeostasis model assessment, and 2-h post-oral glucose tolerance test glucose and insulin levels. ITGA1 has demonstrated genetic pleiotropy in prior studies, and its suggested role in liver fibrosis, insulin secretion, and bone healing lends credence to its contribution to both osteoporosis and type 2 diabetes. These findings further underscore the link between skeletal and glucose metabolism and highlight a locus to direct future investigations. Diabetes 61:2176-2186, 2012

Original language	English
Pages (from-to)	2176-2186
Number of pages	11
Journal	Diabetes
Volume	61
Issue number	8
Early online date	14 Jun 2012
DOIs	https://doi.org/10.2337/db11-1515
Publication status	Published - Aug 2012

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Billings, L. K., Hsu, Y.-H., Ackerman, R. J., Dupuis, J., Voight, B. F., Rasmussen-Torvik, L. J., Hercberg, S., Lathrop, M., Barnes, D., Langenberg, C., Hui, J., Fu, M., Bouatia-Naji, N., Lecoeur, C., An, P., Magnusson, P. K., Surakkaza, I., Ripatti, S., Christiansen, L., ... ASCOT Investigators, DIAGRAM Consortium, MuTHER Consortium, MAGIC Investigators, GEFOS Consortium (2012). Impact of Common Variation in Bone-Related Genes on Type 2 Diabetes and Related Traits. Diabetes, 61(8), 2176-2186. https://doi.org/10.2337/db11-1515

@article{1335850bca9448cb8e7ce549fd728e6c,

title = "Impact of Common Variation in Bone-Related Genes on Type 2 Diabetes and Related Traits",

abstract = "Exploring genetic pleiotropy can provide clues to a mechanism underlying the observed epidemiological association between type 2 diabetes and heightened fracture risk. We examined genetic variants associated with bone mineral density (BMD) for association with type 2 diabetes and glycemic traits in large well-phenotyped and -genotyped consortia. We undertook follow-up analysis in similar to 19,000 individuals and assessed gene expression. We queried single nucleotide polymorphisms (SNPs) associated with BMD at levels of genome-wide significance, variants in linkage disequilibrium (r(2) > 0.5), and BMD candidate genes. SNP rs6867040, at the ITGA1 locus, was associated with a 0.0166 mmol/L (0.004) increase in fasting glucose per C allele in the combined analysis. Genetic variants in the ITGA1 locus were associated with its expression in the liver but not in adipose tissue. ITGA1 variants appeared among the top loci associated with type 2 diabetes, fasting insulin, beta-cell function by homeostasis model assessment, and 2-h post-oral glucose tolerance test glucose and insulin levels. ITGA1 has demonstrated genetic pleiotropy in prior studies, and its suggested role in liver fibrosis, insulin secretion, and bone healing lends credence to its contribution to both osteoporosis and type 2 diabetes. These findings further underscore the link between skeletal and glucose metabolism and highlight a locus to direct future investigations. Diabetes 61:2176-2186, 2012",

author = "Billings, {Liana K.} and Yi-Hsiang Hsu and Ackerman, {Rachel J.} and Josee Dupuis and Voight, {Benjamin F.} and Rasmussen-Torvik, {Laura J.} and Serge Hercberg and Mark Lathrop and Daniel Barnes and Claudia Langenberg and Jennie Hui and Mao Fu and Nabila Bouatia-Naji and Cecile Lecoeur and Ping An and Magnusson, {Patrik K.} and Ida Surakkaza and Samuli Ripatti and Lene Christiansen and Christine Dalgard and Lasse Folkersen and Elin Grundberg and Per Eriksson and Jaakko Kaprio and Kyvik, {Kirsten Ohm} and Pedersen, {Nancy L.} and Borecki, {Ingrid B.} and Province, {Michael A.} and Beverley Balkau and Philippe Froguel and Shuldiner, {Alan R.} and Palmer, {Lyle J.} and Nick Wareham and Pierre Meneton and Toby Johnson and Pankow, {James S.} and David Karasik and Meigs, {James B.} and Kiel, {Douglas P.} and Florez, {Jose C.} and {ASCOT Investigators, DIAGRAM Consortium, MuTHER Consortium, MAGIC Investigators, GEFOS Consortium}",

year = "2012",

month = aug,

doi = "10.2337/db11-1515",

language = "English",

volume = "61",

pages = "2176--2186",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

number = "8",

}

Billings, LK, Hsu, Y-H, Ackerman, RJ, Dupuis, J, Voight, BF, Rasmussen-Torvik, LJ, Hercberg, S, Lathrop, M, Barnes, D, Langenberg, C, Hui, J, Fu, M, Bouatia-Naji, N, Lecoeur, C, An, P, Magnusson, PK, Surakkaza, I, Ripatti, S, Christiansen, L, Dalgard, C, Folkersen, L, Grundberg, E, Eriksson, P, Kaprio, J, Kyvik, KO, Pedersen, NL, Borecki, IB, Province, MA, Balkau, B, Froguel, P, Shuldiner, AR, Palmer, LJ, Wareham, N, Meneton, P, Johnson, T, Pankow, JS, Karasik, D, Meigs, JB, Kiel, DP, Florez, JC & ASCOT Investigators, DIAGRAM Consortium, MuTHER Consortium, MAGIC Investigators, GEFOS Consortium 2012, 'Impact of Common Variation in Bone-Related Genes on Type 2 Diabetes and Related Traits', Diabetes, vol. 61, no. 8, pp. 2176-2186. https://doi.org/10.2337/db11-1515

TY - JOUR

T1 - Impact of Common Variation in Bone-Related Genes on Type 2 Diabetes and Related Traits

AU - Billings, Liana K.

AU - Hsu, Yi-Hsiang

AU - Ackerman, Rachel J.

AU - Dupuis, Josee

AU - Voight, Benjamin F.

AU - Rasmussen-Torvik, Laura J.

AU - Hercberg, Serge

AU - Lathrop, Mark

AU - Barnes, Daniel

AU - Langenberg, Claudia

AU - Hui, Jennie

AU - Fu, Mao

AU - Bouatia-Naji, Nabila

AU - Lecoeur, Cecile

AU - An, Ping

AU - Magnusson, Patrik K.

AU - Surakkaza, Ida

AU - Ripatti, Samuli

AU - Christiansen, Lene

AU - Dalgard, Christine

AU - Folkersen, Lasse

AU - Grundberg, Elin

AU - Eriksson, Per

AU - Kaprio, Jaakko

AU - Kyvik, Kirsten Ohm

AU - Pedersen, Nancy L.

AU - Borecki, Ingrid B.

AU - Province, Michael A.

AU - Balkau, Beverley

AU - Froguel, Philippe

AU - Shuldiner, Alan R.

AU - Palmer, Lyle J.

AU - Wareham, Nick

AU - Meneton, Pierre

AU - Johnson, Toby

AU - Pankow, James S.

AU - Karasik, David

AU - Meigs, James B.

AU - Kiel, Douglas P.

AU - Florez, Jose C.

AU - ASCOT Investigators, DIAGRAM Consortium, MuTHER Consortium, MAGIC Investigators, GEFOS Consortium

PY - 2012/8

Y1 - 2012/8

N2 - Exploring genetic pleiotropy can provide clues to a mechanism underlying the observed epidemiological association between type 2 diabetes and heightened fracture risk. We examined genetic variants associated with bone mineral density (BMD) for association with type 2 diabetes and glycemic traits in large well-phenotyped and -genotyped consortia. We undertook follow-up analysis in similar to 19,000 individuals and assessed gene expression. We queried single nucleotide polymorphisms (SNPs) associated with BMD at levels of genome-wide significance, variants in linkage disequilibrium (r(2) > 0.5), and BMD candidate genes. SNP rs6867040, at the ITGA1 locus, was associated with a 0.0166 mmol/L (0.004) increase in fasting glucose per C allele in the combined analysis. Genetic variants in the ITGA1 locus were associated with its expression in the liver but not in adipose tissue. ITGA1 variants appeared among the top loci associated with type 2 diabetes, fasting insulin, beta-cell function by homeostasis model assessment, and 2-h post-oral glucose tolerance test glucose and insulin levels. ITGA1 has demonstrated genetic pleiotropy in prior studies, and its suggested role in liver fibrosis, insulin secretion, and bone healing lends credence to its contribution to both osteoporosis and type 2 diabetes. These findings further underscore the link between skeletal and glucose metabolism and highlight a locus to direct future investigations. Diabetes 61:2176-2186, 2012

AB - Exploring genetic pleiotropy can provide clues to a mechanism underlying the observed epidemiological association between type 2 diabetes and heightened fracture risk. We examined genetic variants associated with bone mineral density (BMD) for association with type 2 diabetes and glycemic traits in large well-phenotyped and -genotyped consortia. We undertook follow-up analysis in similar to 19,000 individuals and assessed gene expression. We queried single nucleotide polymorphisms (SNPs) associated with BMD at levels of genome-wide significance, variants in linkage disequilibrium (r(2) > 0.5), and BMD candidate genes. SNP rs6867040, at the ITGA1 locus, was associated with a 0.0166 mmol/L (0.004) increase in fasting glucose per C allele in the combined analysis. Genetic variants in the ITGA1 locus were associated with its expression in the liver but not in adipose tissue. ITGA1 variants appeared among the top loci associated with type 2 diabetes, fasting insulin, beta-cell function by homeostasis model assessment, and 2-h post-oral glucose tolerance test glucose and insulin levels. ITGA1 has demonstrated genetic pleiotropy in prior studies, and its suggested role in liver fibrosis, insulin secretion, and bone healing lends credence to its contribution to both osteoporosis and type 2 diabetes. These findings further underscore the link between skeletal and glucose metabolism and highlight a locus to direct future investigations. Diabetes 61:2176-2186, 2012

U2 - 10.2337/db11-1515

DO - 10.2337/db11-1515

M3 - Article

SN - 0012-1797

VL - 61

SP - 2176

EP - 2186

JO - Diabetes

JF - Diabetes

IS - 8

ER -

Impact of Common Variation in Bone-Related Genes on Type 2 Diabetes and Related Traits

Abstract

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