Association of Birth Weight With Type 2 Diabetes and Glycemic Traits: A Mendelian Randomization Study.
BIRTH-GENE (BIG) Study Working Group None., Huang T., Wang T., Zheng Y., Ellervik C., Li X., Gao M., Fang Z., Chai J-F., Ahluwalia TVS., Wang Y., Voortman T., Noordam R., Frazier-Wood A., Scholz M., Sonestedt E., Akiyama M., Dorajoo R., Zhou A., Kilpeläinen TO., Kleber ME., Crozier SR., Godfrey KM., Lemaitre R., Felix JF., Shi Y., Gupta P., Khor C-C., Lehtimäki T., Wang CA., Tiesler CMT., Thiering E., Standl M., Rzehak P., Marouli E., He M., Lecoeur C., Corella D., Lai C-Q., Moreno LA., Pitkänen N., Boreham CA., Zhang T., Saw SM., Ridker PM., Graff M., van Rooij FJA., Uitterlinden AG., Hofman A., van Heemst D., Rosendaal FR., de Mutsert R., Burkhardt R., Schulz C-A., Ericson U., Kamatani Y., Yuan J-M., Power C., Hansen T., Sørensen TIA., Tjønneland A., Overvad K., Delgado G., Cooper C., Djousse L., Rivadeneira F., Jameson K., Zhao W., Liu J., Lee NR., Raitakari O., Kähönen M., Viikari J., Grote V., Langhendries J-P., Koletzko B., Escribano J., Verduci E., Dedoussis G., Yu C., Tham YC., Lim B., Lim SH., Froguel P., Balkau B., Fink NR., Vinding RK., Sevelsted A., Bisgaard H., Coltell O., Dallongeville J., Gottrand F., Pahkala K., Niinikoski H., Hyppönen E., Pedersen O., März W., Inskip H., Jaddoe VWV., Dennison E., Wong TY., Sabanayagam C., Tai E-S., Mohlke KL., Mackey DA., Gruszfeld D., Deloukas P., Tucker KL., Fumeron F., Bønnelykke K., Rossing P., Estruch R., Ordovas JM., Arnett DK., Meirhaeghe A., Amouyel P., Cheng C-Y., Sim X., Teo YY., van Dam RM., Koh W-P., Orho-Melander M., Loeffler M., Kubo M., Thiery J., Mook-Kanamori DO., Mozaffarian D., Psaty BM., Franco OH., Wu T., North KE., Davey Smith G., Chavarro JE., Chasman DI., Qi L.
Importance: Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations. Objective: To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis. Design, Setting, and Participants: This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included. Main Outcomes and Measures: Type 2 diabetes and glycemic traits. Results: This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (β = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration. Conclusions and Relevance: In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms.