A causal analysis using a Mendelian randomization approach Sarah Lewis A few earlier studies Common problems in observational studies Measurement error Reportinginterviewer bias Reverse causation ID: 1045296
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1. Prenatal Nutrition and IQ: A causal analysis using a Mendelianrandomization approachSarah Lewis
2. A few earlier studies
3. Common problems in observational studiesMeasurement errorReporting/interviewer biasReverse causationCONFOUNDING
4. 4
5. Mendelian randomization5 Comparison of groups of individuals defined by genotype should only differ with respect to the locus under study. With control for population structure, there should be little confounding by any behavioural, socioeconomic or physiological factors.
6. Mendel’s second law – the law of independent assortment6“The behaviour of each pair of differentiating characteristics in hybrid union is independent of the other differences between the two original plants, and, further, the hybrid produces just so many kinds of egg and pollen cells as there are possible constant combination forms” Gregor Mendel, 1865.
7. Problems of observational epidemiology can be overcome using genetic variants as proxiesConfoundingReverse causationBiologicalDue to reporting biasMeasurement error7Independent assortmentFixed at conceptionCan be measured (genotyped)
8. Clustered environments and randomised genes (93 phenotypes, 23 SNPs)Phenotype / phenotype4278 pairwise associationsPhenotype / genotype2139 pairwise combinationsGenotype / genotype253 pairwise combinations43% significant at p<0.0120 significant at p<0.01 vs 21 expected4 / 253 significant at p<0.01 vs 3 expectedDavey Smith et al. PLoS Medicine 2008
9. MR Vs RCT9
10. ObjectiveTo determine whether exposure to specific dietary factors in utero and infancy influences cognitionHypothesesSuboptimum levels of nutrients in utero lead to impaired neurodevelopment and cognitive abilityVariation in genes related to nutrient metabolism is associated with neurodevelopment in infancyAssociation of maternal genotype with measurements of cognitive ability, independent of child’s genotype, will indicate a role of the prenatal environment
11. Project designMaternal genetic variants affecting nutrient levelsNutrient exposureIQ at age 8confoundersOffspring genetic variants
12. Association between diet and cognition can be affected by confounding by lifestyle factors, reverse causality and measurement errorPolymorphisms in genes that metabolise nutrients can be used as proxies for differences in dietary intake and therefore to infer causal relationships between nutrients and cognition without the above problems
13. ALSPAC (Avon Longitudinal Study of Parents and Children)Population-based prospective study conducted in Bristol, England to evaluate factors that affect health and development of children~ 14,000 pregnant women enrolled between April 1991 and December 1992Information on mother and child collected at regular intervals and ongoingDNA samples available for mothers and children (~10000 each, ~7000 duos)
14. Population Characteristics
15.
16. Potential ConfoundersMother:AgeEducationSocial classMarital statusParityInter-pregnancy intervalAny infection during pregnancyHousing tenureEver smokedAlcohol consumptionIron, zinc, calcium, folic acid, vitamins, other supplements during pregnancy
17. Potential ConfoundersChild:SexAgeGestationBirth weightBreastfeeding duration
18.
19. Confounders continued
20. Do low levels of vitamin B in utero lead to a lower IQ at age 8?
21. Vitamin B12 factsOnly synthesised by microorganismsMain sources: fish, shellfish, eggs, meat, dairy productsRecommended Daily Amount: 2-3 ug/dayDietary deficiency rare (vegans at risk)B12 deficiency: <150 pmol/lMain functions: red blood cell formation, DNA synthesis, maintenance of healthy nervous systemTransport: 80% bound to transcobalamin I (HC) 20% bound to transcobalamin II (holoTC). holoTC delivers B12 to cells.Stored in the liver
22. indicators of B12 deficiencymodified from Nexo and Hoffmann-Lucke (2011)Birth defectsSpontaneous abortionPre-eclampsiaPrematurityLow birth weightCardiovascular diseaseCognitive deficitDementia
23. Vitamin B12 status during pregnancyand cognition in childrenLower cognition tests scores among offspring of mothers with deficient intake of B12 (Mexico; del Rio Garcia et al., 2009)Children of mothers with low B12 levels performed worse in sustained-attention and working memory tests (India; Bhate et al., 2008)No association of maternal B12 levels with cognitive performance in children. Although verbal ability scores were higher in children of mothers with low B12 (India; Veena et al., 2010)Problem: residual confounding?
24. Observational StudyModel 1: Adjusted for offspring sex and age at time of IQ assessment, and maternal energy intake.Model 2: Model 1 + maternal education, social class, age at delivery, parity, any infection in pregnancy, ever smoked, alcohol consumption before and during pregnancy, folate supplementation.Model 3: Model 2 + gestational length and birth weight.N = 5004mean difference in child IQper doubling of maternal vitamin B12 intake95% CIp-valueModel 12.031.30, 2.76< 0.001Model 20.740.04, 1.440.04Model 30.700.002, 1.390.05
25. Instrumental variables
26. Maternal SNPs vs offspring IQSNPgenotypeNIQ mean (SD)FUT2rs492602TT1009103.3 (16.8)TC1940104.2 (16.1)CC1012105.0 (16.7)mean difference in child IQ per C allele (95% CI)39610.86 (0.14, 1.58)p-value0.02TCN2rs1801198GG784103.9 (16.6)CG1978104.1 (16.0)CC1208104.6 (17.0)mean difference in child IQ per C allele (95% CI)39700.35(-0.38, 1.08)p-value0.35TCN2rs9606756AA3673104.5 (16.0)AG1038104.7 (17.0)GG75108.3 (14.5)mean difference in child IQ per G allele (95% CI)47860.60 (-0.39, 1.58)p-value0.24
27. ConclusionsGenotypes associated with high vitamin B12 levels are associated with higher IQ.However, the effect of genotype on exposure is small, therefore the power of the study to confidently detect an effect is low. Replication is needed.
28. Do low prenatal iron levels affect IQ?
29. Iron deficiency anemia in pregnant womenSource: Worldwide Prevalence of Anemia - WHO report 2008
30. Effects of iron deficiency in early lifedeveloping brain structures (striatum, hippocampus)neurotransmitter systems (dopamine, serotonin)SynaptogenesisMyelinationdifferent gene and protein profiles in the ID brain
31. Consequences for the childrecognition memory functiontemperament (irritability, lower alertness and soothability)hand-eye movementlocomotioncomprehension of languagefine motor skillsschool performancelong lasting abnormalities, even after iron repletion
32. Instruments: TF, TMPRSS6, HFE SNPsrs3811647 G/Aserum transferrinserum ferritintransferrin saturationA = iron loweringBenyamin et al. (2009)rs4820268 A/G D521Dserum ironhaemoglobintransferrin saturationG = iron loweringBenyamin et al. (2009)rs1799945 C/G H63Drs1800562 G/A C282Y serum ironserum transferrinserum ferritinhaemoglobintransferrin saturationC & G= iron loweringKullo et al. (2010)
33. Maternal genotype & Hb levels*p-value adjusted by gestational age at the time of measurement
34. Maternal genotypes and iron supplementationP = 0.001P = 4x10-5
35. Maternal genetic score and child’s IQ
36. dbSNPgenegenotypefull scale IQSDNunadjustedaeffect (95% CI)p-valueNadjusteda,beffect (95% CI)p-valueNrs1799945HFEGG105.917.0790.50 (-0.59, 1.58)0.3735431.09 (-0.27, 2.45)0.392402CG102.916.3850CC104.116.42614rs1800562HFEAA107.112.815-0.52 (-2.05, 1.00)0.5035350.38 (-1.57, 2.32)0.712352GA104.216.6455GG103.816.53065rs3811647TFGG104.016.31511-0.13 (-0.95, 0.69)0.763514-0.36 (-1.40, 0.68)0.502378GA103.916.31613AA103.617.3390rs4820268TMPRSS6AA104.316.0962-0.74 (-1.52, 0.05)0.073527-0.23 (-1.23, 0.77)0.662389AG104.116.71837GG102.716.3728rs1799945/rs18005622 risk alleles0106.116.31560.11 (-0.83, 1.05)0.8234900.99 (-0.19, 2.18)0.1023123 risk alleles1103.116.511634 risk alleles2104.016.42171genotypic score≤3 risk alleles0103.816.1464-0.32 (-0.94, 0.30)0.3134440.22 (-0.54, 0.98)0.5722544 risk alleles1104.416.711435 risk alleles2103.516.113926 risk alleles3103.316.8445Table 5. Maternal genotypes at SNPs in iron-related genes and full scale IQ of their children at 8 years of age.
37. Limitationsinstrument is associated with confoundersupplementation blurs association of genotype and Hbsmall numbers for stratified analysisHFE variants are rare
38. ConclusionsHFE and TMPRSS6 variants were strongly associated with Hb levels. Not so TF rs3811647.Genotypes associated with low Hb levels were also associated with higher risk of iron supplementation.Mothers with rare HFE homozygote genotypes were more likely to have an educational level greater than O-level.The association between iron-related genotypes and child’s IQ was strongest for women who took iron supplements during pregnancy. Adjustment by child’s genotype, maternal education, confounders and ancestry informative markers did not change this result.Results suggest that exposure to low levels of iron in fetal life adversely affects brain development and therefore IQ in childhood.Replication is needed.
39. Lipids and cognitionlipids are vital for membrane biogenesis during cellular growth processes On the other hand, elevated serum cholesterol is a well-known risk factor for cognitive decline, dementia and Alzheimer’s disease. And higher serum LDL has been recently associated with decreased white matter integrity among healthy older adults.
40. Genetic scores for Lipid levelsTG score = 27 SNPsLDL-C score = 35 SNPsHDL-C score = 44 SNPsTC score = 46 SNPs Weighted by effect sizes reported by Teslovich et al. (2010), Aulchenko et al. (2009) and Kettunen et al. (2012) Additive model Risk alleles increase TG, LDL-C and TC, and decrease HDL-C Scores are not associated with confounders
41. Association between offspring lipid genetic scores and plasma lipids, adjusted for age and sex.
42. Association between offspring and maternal genotype scores and offspring IQ
43. Quartiles of LDL-C score, LDL-C plasma levels and IQ in ALSPAC children.
44. ConclusionsScores have been developed which are strongly related to lipid levels.Maternal lipid scores are not associated with offspring IQOffspring LDL score is associated with offspring IQ such that an increase in score increases IQ
45. AcknowledgementsBristol Luisa Zuccolo OxfordCarolina Bonilla David Smith Jean Golding Helga RefsumAndy Ness Yoav Ben-Shlomo AustraliaDavid Gunnell Marie-Jo BrionGeorge Davey Smith Craig PennellDebbie Lawlor Raine team and participantsAmy Taylor Pauline Emmett Nic Timpson Beate St. Pourcain Kate Northstone Phil Lobb & Sue Ring ALSPAC team and participants