Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases.
Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m²) compared to obese cases (BMI≥30 Kg/m²). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m²) or 4,123 obese cases (BMI≥30 kg/m²), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4×10⁻⁹, OR = 1.13 [95% CI 1.09-1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00-1.06]). A variant in HMG20A--previously identified in South Asians but not Europeans--was associated with type 2 diabetes in obese cases (P = 1.3×10⁻⁸, OR = 1.11 [95% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02-1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10-1.17], P = 3.2×10⁻¹⁴. This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05-1.08], P = 2.2×10⁻¹⁶. This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.
Genetics of Complex Traits, Peninsula Medical School, University of Exeter, Exeter, United Kingdom.
John R B
JR
Perry
Benjamin F
BF
Voight
Loïc
L
Yengo
Najaf
N
Amin
Josée
J
Dupuis
Martha
M
Ganser
Harald
H
Grallert
Pau
P
Navarro
Man
M
Li
Lu
L
Qi
Valgerdur
V
Steinthorsdottir
Robert A
RA
Scott
Peter
P
Almgren
Dan E
DE
Arking
Yurii
Y
Aulchenko
Beverley
B
Balkau
Rafn
R
Benediktsson
Richard N
RN
Bergman
Eric
E
Boerwinkle
Lori
L
Bonnycastle
Noël P
NP
Burtt
Harry
H
Campbell
Guillaume
G
Charpentier
Francis S
FS
Collins
Christian
C
Gieger
Todd
T
Green
Samy
S
Hadjadj
Andrew T
AT
Hattersley
Christian
C
Herder
Albert
A
Hofman
Andrew D
AD
Johnson
Anna
A
Kottgen
Peter
P
Kraft
Yann
Y
Labrune
Claudia
C
Langenberg
Alisa K
AK
Manning
Karen L
KL
Mohlke
Andrew P
AP
Morris
Ben
B
Oostra
James
J
Pankow
Ann-Kristin
AK
Petersen
Peter P
PP
Pramstaller
Inga
I
Prokopenko
Wolfgang
W
Rathmann
William
W
Rayner
Michael
M
Roden
Igor
I
Rudan
Denis
D
Rybin
Laura J
LJ
Scott
Gunnar
G
Sigurdsson
Rob
R
Sladek
Gudmar
G
Thorleifsson
Unnur
U
Thorsteinsdottir
Jaakko
J
Tuomilehto
Andre G
AG
Uitterlinden
Sidonie
S
Vivequin
Michael N
MN
Weedon
Alan F
AF
Wright
Frank B
FB
Hu
Thomas
T
Illig
Linda
L
Kao
James B
JB
Meigs
James F
JF
Wilson
Kari
K
Stefansson
Cornelia
C
van Duijn
David
D
Altschuler
Andrew D
AD
Morris
Michael
M
Boehnke
Mark I
MI
McCarthy
Philippe
P
Froguel
Colin N A
CN
Palmer
Nicholas J
NJ
Wareham
Leif
L
Groop
Timothy M
TM
Frayling
Stéphane
S
Cauchi
D000368:Aged; D000483:Alleles; D044466:Asian People / Q000235:genetics; D015992:Body Mass Index; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006609:High Mobility Group Proteins / Q000235:genetics*; D006801:Humans; D007797:Laminin / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People / Q000235:genetics
C408987:HMG20A protein, human; D006609:High Mobility Group Proteins; D007797:Laminin; C084098:laminin A