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Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses.

ABSTRACT: Estimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated individuals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies.

SUBMITTER: Brumpton B

PROVIDER: S-EPMC7360778 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses.

Brumpton Ben B Sanderson Eleanor E Heilbron Karl K Hartwig Fernando Pires FP Harrison Sean S Vie Gunnhild Åberge GÅ Cho Yoonsu Y Howe Laura D LD Hughes Amanda A Boomsma Dorret I DI Havdahl Alexandra A Hopper John J Neale Michael M Nivard Michel G MG Pedersen Nancy L NL Reynolds Chandra A CA Tucker-Drob Elliot M EM Grotzinger Andrew A Howe Laurence L Morris Tim T Li Shuai S Auton Adam A Windmeijer Frank F Chen Wei-Min WM Bjørngaard Johan Håkon JH Hveem Kristian K Willer Cristen C Evans David M DM Kaprio Jaakko J Davey Smith George G Åsvold Bjørn Olav BO Hemani Gibran G Davies Neil M NM

Nature communications 20200714 1

Estimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 sib ...[more]

PMID: 32665587

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Project description:INTRODUCTION:In contact zones, genetic mixing of two taxa can be restricted by prezygotic (e.g. assortative mating) or postzygotic (lower fitness of hybrid offspring) barriers, or a combination of the two. A hybrid zone between two willow warbler subspecies (Phylloscopus trochilus trochilus, P. t. acredula) with distinctive migratory strategies occurs in central Sweden. These subspecies exhibit differences in migratory direction and distance, resulting in geographically distinct wintering areas in Africa. The subspecies may have diverged from a common refuge after the last ice age, and neutral genetic markers are homogeneous across their range. By contrast, several phenotypic traits and genetic markers of two chromosomal regions previously identified show steep clines across the divide. The evolutionary forces that maintain this migratory divide remain unknown. Here we use plumage colour, morphology, genetic markers and feather stable nitrogen-isotopes (? (15)N) to assess if assortative mating between migratory phenotypes could be acting as a possible mechanism for keeping the two forms genetically separate and maintaining the migratory divide. We colour-ringed a willow warbler breeding population in the central part of the hybrid zone and observed the breeding population to assess phenotypic and genotypic traits of social pairs. RESULTS:Our data suggest that wintering area and genetic ancestry had an effect on male arrival time to the breeding grounds which could contribute to assortment. However, evidence for assortative mating could not be detected based on a comparison of plumage colour, morphology and ? (15)N between social mates. CONCLUSION:This finding was strengthened by analyses of subspecies-specific genetic markers, which allowed us to identify the presence of a large proportion of potential hybrids and backcrosses at the study site. Our results supported the hypothesis that pre-mating isolation in willow warblers is weak, resulting in extensive hybridisation across the migratory divide.

Dataset Information

Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses.

Publications

Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses.

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