Exploring a causal role of DNA methylation in the relationship between maternal vitamin B12 during pregnancy and child's IQ at age 8, cognitive performance and educational attainment: A two-step Mendelian randomization study

Doretta Caramaschi, Gemma C Sharp, Ellen A Nohr, Katie Berryman, Sarah J Lewis, George Davey Smith, Caroline L Relton

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Resumé

An adequate intake of vitamin B12 during pregnancy plays an important role in offspring neurodevelopment, potentially via epigenetic processes. We used a two-step Mendelian randomization approach to assess whether DNA methylation plays a mediating and causal role in associations between maternal vitamin B12 status and offspring's cognition. Firstly, we estimated the causal effect of maternal vitamin B12 levels on cord blood DNA methylation using the maternal FUT2 genotypes rs492602:A > G and rs1047781:A > T as proxies for circulating vitamin B12 levels in the Avon Longitudinal Study of Parents and Children (ALSPAC) and we tested the observed associations in a replication cohort. Secondly, we estimated the causal effect of DNA methylation on IQ using the offspring genotype at sites close to the methylated CpG site as a proxy for DNA methylation in ALSPAC and in a replication sample. The first step Mendelian randomization estimated that maternal vitamin B12 had a small causal effect on DNA methylation in offspring at three CpG sites, which was replicated for one of the sites. The second step Mendelian randomization found weak evidence of a causal effect of DNA methylation at two of these sites on childhood performance IQ which was replicated for one of the sites. The findings support a causal effect of maternal vitamin B12 levels on cord blood DNA methylation, and a causal effect of vitamin B12-responsive DNA methylation changes on children's cognition. Some limitations were identified and future studies using a similar approach should aim to overcome such issues.

OriginalsprogEngelsk
TidsskriftHuman Molecular Genetics
Vol/bind26
Udgave nummer15
Sider (fra-til)3001-3013
ISSN0964-6906
DOI
StatusUdgivet - 1. aug. 2017

Fingeraftryk

DNA Methylation
Random Allocation
Mothers
Proxy
Fetal Blood
Cognition
Longitudinal Studies
Parents

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title = "Exploring a causal role of DNA methylation in the relationship between maternal vitamin B12 during pregnancy and child's IQ at age 8, cognitive performance and educational attainment: A two-step Mendelian randomization study",
abstract = "An adequate intake of vitamin B12 during pregnancy plays an important role in offspring neurodevelopment, potentially via epigenetic processes. We used a two-step Mendelian randomization approach to assess whether DNA methylation plays a mediating and causal role in associations between maternal vitamin B12 status and offspring's cognition. Firstly, we estimated the causal effect of maternal vitamin B12 levels on cord blood DNA methylation using the maternal FUT2 genotypes rs492602:A > G and rs1047781:A > T as proxies for circulating vitamin B12 levels in the Avon Longitudinal Study of Parents and Children (ALSPAC) and we tested the observed associations in a replication cohort. Secondly, we estimated the causal effect of DNA methylation on IQ using the offspring genotype at sites close to the methylated CpG site as a proxy for DNA methylation in ALSPAC and in a replication sample. The first step Mendelian randomization estimated that maternal vitamin B12 had a small causal effect on DNA methylation in offspring at three CpG sites, which was replicated for one of the sites. The second step Mendelian randomization found weak evidence of a causal effect of DNA methylation at two of these sites on childhood performance IQ which was replicated for one of the sites. The findings support a causal effect of maternal vitamin B12 levels on cord blood DNA methylation, and a causal effect of vitamin B12-responsive DNA methylation changes on children's cognition. Some limitations were identified and future studies using a similar approach should aim to overcome such issues.",
keywords = "Adult, Child, Cognition/drug effects, DNA Methylation/genetics, Epigenesis, Genetic/genetics, Family, Female, Fetal Blood/metabolism, Genotype, Humans, Intelligence Tests, Intelligence/drug effects, Longitudinal Studies, Male, Mendelian Randomization Analysis, Pregnancy, Prenatal Exposure Delayed Effects/genetics, Random Allocation, Vitamin B 12/metabolism",
author = "Doretta Caramaschi and Sharp, {Gemma C} and Nohr, {Ellen A} and Katie Berryman and Lewis, {Sarah J} and {Davey Smith}, George and Relton, {Caroline L}",
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pages = "3001--3013",
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Exploring a causal role of DNA methylation in the relationship between maternal vitamin B12 during pregnancy and child's IQ at age 8, cognitive performance and educational attainment : A two-step Mendelian randomization study. / Caramaschi, Doretta; Sharp, Gemma C; Nohr, Ellen A; Berryman, Katie; Lewis, Sarah J; Davey Smith, George; Relton, Caroline L.

I: Human Molecular Genetics, Bind 26, Nr. 15, 01.08.2017, s. 3001-3013.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Exploring a causal role of DNA methylation in the relationship between maternal vitamin B12 during pregnancy and child's IQ at age 8, cognitive performance and educational attainment

T2 - A two-step Mendelian randomization study

AU - Caramaschi, Doretta

AU - Sharp, Gemma C

AU - Nohr, Ellen A

AU - Berryman, Katie

AU - Lewis, Sarah J

AU - Davey Smith, George

AU - Relton, Caroline L

N1 - © The Author 2017. Published by Oxford University Press.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - An adequate intake of vitamin B12 during pregnancy plays an important role in offspring neurodevelopment, potentially via epigenetic processes. We used a two-step Mendelian randomization approach to assess whether DNA methylation plays a mediating and causal role in associations between maternal vitamin B12 status and offspring's cognition. Firstly, we estimated the causal effect of maternal vitamin B12 levels on cord blood DNA methylation using the maternal FUT2 genotypes rs492602:A > G and rs1047781:A > T as proxies for circulating vitamin B12 levels in the Avon Longitudinal Study of Parents and Children (ALSPAC) and we tested the observed associations in a replication cohort. Secondly, we estimated the causal effect of DNA methylation on IQ using the offspring genotype at sites close to the methylated CpG site as a proxy for DNA methylation in ALSPAC and in a replication sample. The first step Mendelian randomization estimated that maternal vitamin B12 had a small causal effect on DNA methylation in offspring at three CpG sites, which was replicated for one of the sites. The second step Mendelian randomization found weak evidence of a causal effect of DNA methylation at two of these sites on childhood performance IQ which was replicated for one of the sites. The findings support a causal effect of maternal vitamin B12 levels on cord blood DNA methylation, and a causal effect of vitamin B12-responsive DNA methylation changes on children's cognition. Some limitations were identified and future studies using a similar approach should aim to overcome such issues.

AB - An adequate intake of vitamin B12 during pregnancy plays an important role in offspring neurodevelopment, potentially via epigenetic processes. We used a two-step Mendelian randomization approach to assess whether DNA methylation plays a mediating and causal role in associations between maternal vitamin B12 status and offspring's cognition. Firstly, we estimated the causal effect of maternal vitamin B12 levels on cord blood DNA methylation using the maternal FUT2 genotypes rs492602:A > G and rs1047781:A > T as proxies for circulating vitamin B12 levels in the Avon Longitudinal Study of Parents and Children (ALSPAC) and we tested the observed associations in a replication cohort. Secondly, we estimated the causal effect of DNA methylation on IQ using the offspring genotype at sites close to the methylated CpG site as a proxy for DNA methylation in ALSPAC and in a replication sample. The first step Mendelian randomization estimated that maternal vitamin B12 had a small causal effect on DNA methylation in offspring at three CpG sites, which was replicated for one of the sites. The second step Mendelian randomization found weak evidence of a causal effect of DNA methylation at two of these sites on childhood performance IQ which was replicated for one of the sites. The findings support a causal effect of maternal vitamin B12 levels on cord blood DNA methylation, and a causal effect of vitamin B12-responsive DNA methylation changes on children's cognition. Some limitations were identified and future studies using a similar approach should aim to overcome such issues.

KW - Adult

KW - Child

KW - Cognition/drug effects

KW - DNA Methylation/genetics

KW - Epigenesis, Genetic/genetics

KW - Family

KW - Female

KW - Fetal Blood/metabolism

KW - Genotype

KW - Humans

KW - Intelligence Tests

KW - Intelligence/drug effects

KW - Longitudinal Studies

KW - Male

KW - Mendelian Randomization Analysis

KW - Pregnancy

KW - Prenatal Exposure Delayed Effects/genetics

KW - Random Allocation

KW - Vitamin B 12/metabolism

U2 - 10.1093/hmg/ddx164

DO - 10.1093/hmg/ddx164

M3 - Journal article

C2 - 28453778

VL - 26

SP - 3001

EP - 3013

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 15

ER -