Examination of type 2 diabetes loci implicates CDKAL1 as a birth weight gene.
OBJECTIVE
A number of studies have found that reduced birth weight is associated with type 2 diabetes later in life; however, the underlying mechanism for this correlation remains unresolved. Recently, association has been demonstrated between low birth weight and single nucleotide polymorphisms (SNPs) at the CDKAL1 and HHEX-IDE loci, regions that were previously implicated in the pathogenesis of type 2 diabetes. In order to investigate whether type 2 diabetes risk-conferring alleles associate with low birth weight in our Caucasian childhood cohort, we examined the effects of 20 such loci on this trait.


METHODS
Using data from an ongoing genome-wide association study in our cohort of 5,465 Caucasian children with recorded birth weights, we investigated the association of the previously reported type 2 diabetes-associated variation at 20 loci including TCF7L2, HHEX-IDE, PPARG, KCNJ11, SLC30A8, IGF2BP2, CDKAL1, CDKN2A/2B, and JAZF1 with birth weight.


RESULTS
Our data show that the minor allele of rs7756992 (P = 8 x 10(-5)) at the CDKAL1 locus is strongly associated with lower birth weight, whereas a perfect surrogate for variation previously implicated for the trait at the same locus only yielded nominally significant association (P = 0.01; r(2) rs7756992 = 0.677). However, association was not detected with any of the other type 2 diabetes loci studied.


CONCLUSIONS
We observe association between lower birth weight and type 2 diabetes risk-conferring alleles at the CDKAL1 locus. Our data show that the same genetic locus that has been identified as a marker for type 2 diabetes in previous studies also influences birth weight.
Zhao
Jianhua
J
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Li
Mingyao
M
Bradfield
Jonathan P
JP
Wang
Kai
K
Zhang
Haitao
H
Sleiman
Patrick
P
Kim
Cecilia E
CE
Annaiah
Kiran
K
Glaberson
Wendy
W
Glessner
Joseph T
JT
Otieno
F George
FG
Thomas
Kelly A
KA
Garris
Maria
M
Hou
Cuiping
C
Frackelton
Edward C
EC
Chiavacci
Rosetta M
RM
Berkowitz
Robert I
RI
Hakonarson
Hakon
H
Grant
Struan F A
SF
D001724:Birth Weight / Q000235:genetics*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D015143:Philadelphia; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics; D012359:tRNA Methyltransferases
D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human