Impact of common variation in bone-related genes on type 2 diabetes and related traits.
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 ∼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, β-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.
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Liana K
LK
Billings
Yi-Hsiang
YH
Hsu
Rachel J
RJ
Ackerman
Josée
J
Dupuis
Benjamin F
BF
Voight
Laura J
LJ
Rasmussen-Torvik
Serge
S
Hercberg
Mark
M
Lathrop
Daniel
D
Barnes
Claudia
C
Langenberg
Jennie
J
Hui
Mao
M
Fu
Nabila
N
Bouatia-Naji
Cecile
C
Lecoeur
Ping
P
An
Patrik K
PK
Magnusson
Ida
I
Surakka
Samuli
S
Ripatti
Lene
L
Christiansen
Christine
C
Dalgård
Lasse
L
Folkersen
Elin
E
Grundberg
Per
P
Eriksson
Jaakko
J
Kaprio
Kirsten
K
Ohm Kyvik
Nancy L
NL
Pedersen
Ingrid B
IB
Borecki
Michael A
MA
Province
Beverley
B
Balkau
Philippe
P
Froguel
Alan R
AR
Shuldiner
Lyle J
LJ
Palmer
Nick
N
Wareham
Pierre
P
Meneton
Toby
T
Johnson
James S
JS
Pankow
David
D
Karasik
James B
JB
Meigs
Douglas P
DP
Kiel
Jose C
JC
Florez
D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism; D015992:Body Mass Index; D015519:Bone Density / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004720:Endonucleases; D005260:Female; D050723:Fractures, Bone / Q000209:etiology* / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D007328:Insulin / Q000235:genetics; D039423:Integrin alpha1 / Q000235:genetics*; D015810:Linkage Disequilibrium; D008099:Liver / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics; D009687:Nuclear Proteins; D010024:Osteoporosis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
D001786:Blood Glucose; D007328:Insulin; D039423:Integrin alpha1; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D004720:Endonucleases; C550527:pelo protein, human