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Association of birth weight with type 2 diabetes and glycemic traits: A Mendelian randomization study

Association of birth weight with type 2 diabetes and glycemic traits: A Mendelian randomization study
Association of birth weight with type 2 diabetes and glycemic traits: A Mendelian randomization study
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.
Crozier, Sarah
9c3595ce-45b0-44fa-8c4c-4c555e628a03
Godfrey, Keith
0931701e-fe2c-44b5-8f0d-ec5c7477a6fd
Cooper, Cyrus
e05f5612-b493-4273-9b71-9e0ce32bdad6
Jameson, Karen
d5fb142d-06af-456e-9016-17497f94e9f2
Inskip, Hazel
5fb4470a-9379-49b2-a533-9da8e61058b7
Dennison, Elaine
ee647287-edb4-4392-8361-e59fd505b1d1
BIRTH-GENE (BIG) Study Working Group
Crozier, Sarah
9c3595ce-45b0-44fa-8c4c-4c555e628a03
Godfrey, Keith
0931701e-fe2c-44b5-8f0d-ec5c7477a6fd
Cooper, Cyrus
e05f5612-b493-4273-9b71-9e0ce32bdad6
Jameson, Karen
d5fb142d-06af-456e-9016-17497f94e9f2
Inskip, Hazel
5fb4470a-9379-49b2-a533-9da8e61058b7
Dennison, Elaine
ee647287-edb4-4392-8361-e59fd505b1d1

BIRTH-GENE (BIG) Study Working Group (2019) Association of birth weight with type 2 diabetes and glycemic traits: A Mendelian randomization study. JAMA Network Open, 2 (9). (doi:10.1001/jamanetworkopen.2019.10915).

Record type: Article

Abstract

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.

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Accepted/In Press date: 31 May 2019
e-pub ahead of print date: 20 September 2019

Identifiers

Local EPrints ID: 435247
URI: http://eprints.soton.ac.uk/id/eprint/435247
PURE UUID: 385b387b-3842-483a-b8b2-96005395216c
ORCID for Sarah Crozier: ORCID iD orcid.org/0000-0002-9524-1127
ORCID for Keith Godfrey: ORCID iD orcid.org/0000-0002-4643-0618
ORCID for Cyrus Cooper: ORCID iD orcid.org/0000-0003-3510-0709
ORCID for Hazel Inskip: ORCID iD orcid.org/0000-0001-8897-1749
ORCID for Elaine Dennison: ORCID iD orcid.org/0000-0002-3048-4961

Catalogue record

Date deposited: 28 Oct 2019 17:30
Last modified: 26 Nov 2021 02:44

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Contributors

Author: Sarah Crozier ORCID iD
Author: Keith Godfrey ORCID iD
Author: Cyrus Cooper ORCID iD
Author: Karen Jameson
Author: Hazel Inskip ORCID iD
Author: Elaine Dennison ORCID iD
Corporate Author: BIRTH-GENE (BIG) Study Working Group

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