Metabolic drivers of dysglycemia in pregnancy: ethnic-specific GWAS of 146 metabolites and 1-sample Mendelian randomization analyses in a UK multi-ethnic birth cohort
IntroductionGestational diabetes mellitus (GDM) is the most common pregnancy complication worldwide and is associated with short- and long-term health implications for both mother and child. Prevalence of GDM varies between ethnicities, with South Asians (SAs) experiencing up to three times the risk...
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| Format: | Article |
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2023.1157416/full |
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| author | Harriett Fuller Harriett Fuller Mark M. Iles Mark M. Iles J. Bernadette Moore Michael A. Zulyniak |
| author_facet | Harriett Fuller Harriett Fuller Mark M. Iles Mark M. Iles J. Bernadette Moore Michael A. Zulyniak |
| author_sort | Harriett Fuller |
| collection | DOAJ |
| description | IntroductionGestational diabetes mellitus (GDM) is the most common pregnancy complication worldwide and is associated with short- and long-term health implications for both mother and child. Prevalence of GDM varies between ethnicities, with South Asians (SAs) experiencing up to three times the risk compared to white Europeans (WEs). Recent evidence suggests that underlying metabolic difference contribute to this disparity, but an investigation of causality is required.MethodsTo address this, we paired metabolite and genomic data to evaluate the causal effect of 146 distinct metabolic characteristics on gestational dysglycemia in SAs and WEs. First, we performed 292 GWASs to identify ethnic-specific genetic variants associated with each metabolite (P ≤ 1 x 10-5) in the Born and Bradford cohort (3688 SA and 3354 WE women). Following this, a one-sample Mendelian Randomisation (MR) approach was applied for each metabolite against fasting glucose and 2-hr post glucose at 26-28 weeks gestation. Additional GWAS and MR on 22 composite measures of metabolite classes were also conducted.ResultsThis study identified 15 novel genome-wide significant (GWS) SNPs associated with tyrosine in the FOXN and SLC13A2 genes and 1 novel GWS SNP (currently in no known gene) associated with acetate in SAs. Using MR approach, 14 metabolites were found to be associated with postprandial glucose in WEs, while in SAs a distinct panel of 11 metabolites were identified. Interestingly, in WEs, cholesterols were the dominant metabolite class driving with dysglycemia, while in SAs saturated fatty acids and total fatty acids were most commonly associated with dysglycemia.DiscussionIn summary, we confirm and demonstrate the presence of ethnic-specific causal relationships between metabolites and dysglycemia in mid-pregnancy in a UK population of SA and WE pregnant women. Future work will aim to investigate their biological mechanisms on dysglycemia and translating this work towards ethnically tailored GDM prevention strategies. |
| first_indexed | 2024-04-09T12:38:52Z |
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| id | doaj.art-938836e0b7f84468a595e2cfae73ecb9 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-09T12:38:52Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-938836e0b7f84468a595e2cfae73ecb92023-05-15T05:06:22ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922023-05-011410.3389/fendo.2023.11574161157416Metabolic drivers of dysglycemia in pregnancy: ethnic-specific GWAS of 146 metabolites and 1-sample Mendelian randomization analyses in a UK multi-ethnic birth cohortHarriett Fuller0Harriett Fuller1Mark M. Iles2Mark M. Iles3J. Bernadette Moore4Michael A. Zulyniak5School of Food Science and Nutrition, University of Leeds, Leeds, United KingdomPublic Health Science Division, Fred Hutchinson Cancer Center, Seattle, WA, United StatesLeeds Institute of Medical Research, University of Leeds, Leeds, United KingdomLeeds Institute for Data Analytics, University of Leeds, Leeds, United KingdomSchool of Food Science and Nutrition, University of Leeds, Leeds, United KingdomSchool of Food Science and Nutrition, University of Leeds, Leeds, United KingdomIntroductionGestational diabetes mellitus (GDM) is the most common pregnancy complication worldwide and is associated with short- and long-term health implications for both mother and child. Prevalence of GDM varies between ethnicities, with South Asians (SAs) experiencing up to three times the risk compared to white Europeans (WEs). Recent evidence suggests that underlying metabolic difference contribute to this disparity, but an investigation of causality is required.MethodsTo address this, we paired metabolite and genomic data to evaluate the causal effect of 146 distinct metabolic characteristics on gestational dysglycemia in SAs and WEs. First, we performed 292 GWASs to identify ethnic-specific genetic variants associated with each metabolite (P ≤ 1 x 10-5) in the Born and Bradford cohort (3688 SA and 3354 WE women). Following this, a one-sample Mendelian Randomisation (MR) approach was applied for each metabolite against fasting glucose and 2-hr post glucose at 26-28 weeks gestation. Additional GWAS and MR on 22 composite measures of metabolite classes were also conducted.ResultsThis study identified 15 novel genome-wide significant (GWS) SNPs associated with tyrosine in the FOXN and SLC13A2 genes and 1 novel GWS SNP (currently in no known gene) associated with acetate in SAs. Using MR approach, 14 metabolites were found to be associated with postprandial glucose in WEs, while in SAs a distinct panel of 11 metabolites were identified. Interestingly, in WEs, cholesterols were the dominant metabolite class driving with dysglycemia, while in SAs saturated fatty acids and total fatty acids were most commonly associated with dysglycemia.DiscussionIn summary, we confirm and demonstrate the presence of ethnic-specific causal relationships between metabolites and dysglycemia in mid-pregnancy in a UK population of SA and WE pregnant women. Future work will aim to investigate their biological mechanisms on dysglycemia and translating this work towards ethnically tailored GDM prevention strategies.https://www.frontiersin.org/articles/10.3389/fendo.2023.1157416/fullgeneticsGDMgestational diabetesSouth Asianmetabolismglucose |
| spellingShingle | Harriett Fuller Harriett Fuller Mark M. Iles Mark M. Iles J. Bernadette Moore Michael A. Zulyniak Metabolic drivers of dysglycemia in pregnancy: ethnic-specific GWAS of 146 metabolites and 1-sample Mendelian randomization analyses in a UK multi-ethnic birth cohort Frontiers in Endocrinology genetics GDM gestational diabetes South Asian metabolism glucose |
| title | Metabolic drivers of dysglycemia in pregnancy: ethnic-specific GWAS of 146 metabolites and 1-sample Mendelian randomization analyses in a UK multi-ethnic birth cohort |
| title_full | Metabolic drivers of dysglycemia in pregnancy: ethnic-specific GWAS of 146 metabolites and 1-sample Mendelian randomization analyses in a UK multi-ethnic birth cohort |
| title_fullStr | Metabolic drivers of dysglycemia in pregnancy: ethnic-specific GWAS of 146 metabolites and 1-sample Mendelian randomization analyses in a UK multi-ethnic birth cohort |
| title_full_unstemmed | Metabolic drivers of dysglycemia in pregnancy: ethnic-specific GWAS of 146 metabolites and 1-sample Mendelian randomization analyses in a UK multi-ethnic birth cohort |
| title_short | Metabolic drivers of dysglycemia in pregnancy: ethnic-specific GWAS of 146 metabolites and 1-sample Mendelian randomization analyses in a UK multi-ethnic birth cohort |
| title_sort | metabolic drivers of dysglycemia in pregnancy ethnic specific gwas of 146 metabolites and 1 sample mendelian randomization analyses in a uk multi ethnic birth cohort |
| topic | genetics GDM gestational diabetes South Asian metabolism glucose |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2023.1157416/full |
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