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MR-PheWAS: hypothesis prioritization among potential causal effects of body mass index on many outcomes, using Mendelian randomization.

Millard LA, Davies NM, Timpson NJ, Tilling K, Flach PA, Davey Smith G - Sci Rep (2015)

Bottom Line: We found 21 of the 172 outcomes were associated with the allele score at an unadjusted p < 0.05 threshold, and use Bonferroni corrections, permutation testing and estimates of the false discovery rate to consider the strength of results given the number of tests performed.The most strongly associated outcomes included leptin, lipid profile, and blood pressure.We also found novel evidence of effects of BMI on a global self-worth score.

View Article: PubMed Central - PubMed

Affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, University of Bristol, Bristol.

ABSTRACT
Observational cohort studies can provide rich datasets with a diverse range of phenotypic variables. However, hypothesis-driven epidemiological analyses by definition only test particular hypotheses chosen by researchers. Furthermore, observational analyses may not provide robust evidence of causality, as they are susceptible to confounding, reverse causation and measurement error. Using body mass index (BMI) as an exemplar, we demonstrate a novel extension to the phenome-wide association study (pheWAS) approach, using automated screening with genotypic instruments to screen for causal associations amongst any number of phenotypic outcomes. We used a sample of 8,121 children from the ALSPAC dataset, and tested the linear association of a BMI-associated allele score with 172 phenotypic outcomes (with variable sample sizes). We also performed an instrumental variable analysis to estimate the causal effect of BMI on each phenotype. We found 21 of the 172 outcomes were associated with the allele score at an unadjusted p < 0.05 threshold, and use Bonferroni corrections, permutation testing and estimates of the false discovery rate to consider the strength of results given the number of tests performed. The most strongly associated outcomes included leptin, lipid profile, and blood pressure. We also found novel evidence of effects of BMI on a global self-worth score.

No MeSH data available.


Related in: MedlinePlus

Testing invalidity of IV assumptions: associations of two instrumental variables using distinct SNP subsets, of binary outcomes.Odds ratio between outcome groups, for a 1 SD change of log BMI aged 8. Comparison between the SNP subsets: (1) 31 SNPs (excluding FTO SNP) and (2) the FTO SNP only. IV estimate of effect using two-stage least squared regression of log BMI at age 8 as the exposure. Graphical illustration of the results in Table 5. Categories for binary variables are given in Supplementary Table 7.
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f5: Testing invalidity of IV assumptions: associations of two instrumental variables using distinct SNP subsets, of binary outcomes.Odds ratio between outcome groups, for a 1 SD change of log BMI aged 8. Comparison between the SNP subsets: (1) 31 SNPs (excluding FTO SNP) and (2) the FTO SNP only. IV estimate of effect using two-stage least squared regression of log BMI at age 8 as the exposure. Graphical illustration of the results in Table 5. Categories for binary variables are given in Supplementary Table 7.

Mentions: The 31 SNP score and FTO allele were both strong instruments for log BMI at age 8. A 1 SD increase of the 31-SNP score was associated with a 0.146 standard deviation increase in log BMI at age 8 (95% CI: 0.12, 0.17, F = 112.70). A 1 SD increase of FTO was associated with a 0.074 standard deviation increase in log BMI at age 8 (95% CI: 0.05, 0.10, F = 28.18). We found little evidence of pleiotropy, linkage disequilibrium or population stratification as the tests with the FTO and 31-SNP scores were highly consistent (Figs 4 and 5 and Table 5). We found evidence using the Hansen tests of differences between the estimated effects of BMI using each instrument for 5 outcomes: apolipoprotein AI, apolipoprotein B, insulin, leptin and the emotional symptoms score (Table 6). This may be due to chance, or alternatively may suggest that the genetic variants related to BMI have pleiotropic or heterogeneous effects on these outcomes.


MR-PheWAS: hypothesis prioritization among potential causal effects of body mass index on many outcomes, using Mendelian randomization.

Millard LA, Davies NM, Timpson NJ, Tilling K, Flach PA, Davey Smith G - Sci Rep (2015)

Testing invalidity of IV assumptions: associations of two instrumental variables using distinct SNP subsets, of binary outcomes.Odds ratio between outcome groups, for a 1 SD change of log BMI aged 8. Comparison between the SNP subsets: (1) 31 SNPs (excluding FTO SNP) and (2) the FTO SNP only. IV estimate of effect using two-stage least squared regression of log BMI at age 8 as the exposure. Graphical illustration of the results in Table 5. Categories for binary variables are given in Supplementary Table 7.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4644974&req=5

f5: Testing invalidity of IV assumptions: associations of two instrumental variables using distinct SNP subsets, of binary outcomes.Odds ratio between outcome groups, for a 1 SD change of log BMI aged 8. Comparison between the SNP subsets: (1) 31 SNPs (excluding FTO SNP) and (2) the FTO SNP only. IV estimate of effect using two-stage least squared regression of log BMI at age 8 as the exposure. Graphical illustration of the results in Table 5. Categories for binary variables are given in Supplementary Table 7.
Mentions: The 31 SNP score and FTO allele were both strong instruments for log BMI at age 8. A 1 SD increase of the 31-SNP score was associated with a 0.146 standard deviation increase in log BMI at age 8 (95% CI: 0.12, 0.17, F = 112.70). A 1 SD increase of FTO was associated with a 0.074 standard deviation increase in log BMI at age 8 (95% CI: 0.05, 0.10, F = 28.18). We found little evidence of pleiotropy, linkage disequilibrium or population stratification as the tests with the FTO and 31-SNP scores were highly consistent (Figs 4 and 5 and Table 5). We found evidence using the Hansen tests of differences between the estimated effects of BMI using each instrument for 5 outcomes: apolipoprotein AI, apolipoprotein B, insulin, leptin and the emotional symptoms score (Table 6). This may be due to chance, or alternatively may suggest that the genetic variants related to BMI have pleiotropic or heterogeneous effects on these outcomes.

Bottom Line: We found 21 of the 172 outcomes were associated with the allele score at an unadjusted p < 0.05 threshold, and use Bonferroni corrections, permutation testing and estimates of the false discovery rate to consider the strength of results given the number of tests performed.The most strongly associated outcomes included leptin, lipid profile, and blood pressure.We also found novel evidence of effects of BMI on a global self-worth score.

View Article: PubMed Central - PubMed

Affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, University of Bristol, Bristol.

ABSTRACT
Observational cohort studies can provide rich datasets with a diverse range of phenotypic variables. However, hypothesis-driven epidemiological analyses by definition only test particular hypotheses chosen by researchers. Furthermore, observational analyses may not provide robust evidence of causality, as they are susceptible to confounding, reverse causation and measurement error. Using body mass index (BMI) as an exemplar, we demonstrate a novel extension to the phenome-wide association study (pheWAS) approach, using automated screening with genotypic instruments to screen for causal associations amongst any number of phenotypic outcomes. We used a sample of 8,121 children from the ALSPAC dataset, and tested the linear association of a BMI-associated allele score with 172 phenotypic outcomes (with variable sample sizes). We also performed an instrumental variable analysis to estimate the causal effect of BMI on each phenotype. We found 21 of the 172 outcomes were associated with the allele score at an unadjusted p < 0.05 threshold, and use Bonferroni corrections, permutation testing and estimates of the false discovery rate to consider the strength of results given the number of tests performed. The most strongly associated outcomes included leptin, lipid profile, and blood pressure. We also found novel evidence of effects of BMI on a global self-worth score.

No MeSH data available.


Related in: MedlinePlus