Examination of all type 2 diabetes GWAS loci reveals HHEX-IDE as a locus influencing pediatric BMI.
OBJECTIVE
A number of studies have found that BMI in early life influences the risk of developing type 2 diabetes later in life. Our goal was to investigate if any type 2 diabetes variants uncovered through genome-wide association studies (GWAS) impact BMI in childhood.


METHODS
Using data from an ongoing GWAS of pediatric BMI in our cohort, we investigated the association of pediatric BMI with 20 single nucleotide polymorphisms at 18 type 2 diabetes loci uncovered through GWAS, consisting of ADAMTS9, CDC123-CAMK1D, CDKAL1, CDKN2A/B, EXT2, FTO, HHEX-IDE, IGF2BP2, the intragenic region on 11p12, JAZF1, KCNQ1, LOC387761, MTNR1B, NOTCH2, SLC30A8, TCF7L2, THADA, and TSPAN8-LGR5. We randomly partitioned our cohort exactly in half in order to have a discovery cohort (n = 3,592) and a replication cohort (n = 3,592).


RESULTS
Our data show that the major type 2 diabetes risk-conferring G allele of rs7923837 at the HHEX-IDE locus was associated with higher pediatric BMI in both the discovery (P = 0.0013 and survived correction for 20 tests) and replication (P = 0.023) sets (combined P = 1.01 x 10(-4)). Association was not detected with any other known type 2 diabetes loci uncovered to date through GWAS except for the well-established FTO.


CONCLUSIONS
Our data show that the same genetic HHEX-IDE variant, which is associated with type 2 diabetes from previous studies, also influences pediatric BMI.
Zhao
Jianhua
J
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Bradfield
Jonathan P
JP
Zhang
Haitao
H
Annaiah
Kiran
K
Wang
Kai
K
Kim
Cecilia E
CE
Glessner
Joseph T
JT
Frackelton
Edward C
EC
Otieno
F George
FG
Doran
James
J
Thomas
Kelly A
KA
Garris
Maria
M
Hou
Cuiping
C
Chiavacci
Rosetta M
RM
Li
Mingyao
M
Berkowitz
Robert I
RI
Hakonarson
Hakon
H
Grant
Struan F A
SF
D000293:Adolescent; D015992:Body Mass Index; D002648:Child; D002675:Child, Preschool; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics; D007339:Insulysin / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics*
C078492:HHEX protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors; D007339:Insulysin