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  • Multiplex genomewide association analysis of breast milk fatty acid composition extends the phenotypic association and potential selection of FADS1 variants to arachidonic acid, a critical infant micronutrient

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Complex traits
Original article
Multiplex genomewide association analysis of breast milk fatty acid composition extends the phenotypic association and potential selection of FADS1 variants to arachidonic acid, a critical infant micronutrient
  1. Josyf C Mychaleckyj1,
  2. Uma Nayak1,
  3. E Ross Colgate2,
  4. Dadong Zhang3,
  5. Tommy Carstensen4,
  6. Shahnawaz Ahmed5,
  7. Tahmeed Ahmed6,
  8. Alexander J Mentzer7,
  9. Masud Alam6,
  10. Beth D Kirkpatrick2,
  11. Rashidul Haque6,
  12. Abu Syed Golam Faruque5,
  13. William A Petri Jr8
  1. 1 Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA
  2. 2 Department of Medicine, Vaccine Testing Center, University of Vermont, College of Medicine, Burlington, Vermont, USA
  3. 3 Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA
  4. 4 Wellcome Trust Sanger Institute, Cambridge, UK
  5. 5 Center for Nutrition and Food Security, International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
  6. 6 International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
  7. 7 Wellcome Trust Centre for Human Genetics, Oxford, UK
  8. 8 Division of Infectious Diseases and International Health, Department of Medicine, Department of Pathology, University of Virginia, Charlottesville, Virginia, USA
  1. Correspondence to Dr Josyf C Mychaleckyj, Center for Public Health Genomics and Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908-0717, USA; jcm6t{at}virginia.edu

Abstract

Background Breast milk is the sole nutrition source during exclusive breastfeeding, and polyunsaturated fatty acids (FAs) are critical micronutrients in infant physical and cognitive development. There has been no prior genomewide association study of breast milk, hence our objective was to test for genetic association with breast milk FA composition.

Methods We measured the fractional composition of 26 individual FAs in breast milk samples from three cohorts totalling 1142 Bangladeshi mothers whose infants were genotyped on the Illumina MEGA chip and replicated on a custom Affymetrix 30K SNP array (n=616). Maternal genotypes were imputed using IMPUTE.

Results After running 33 separate FA fraction phenotypes, we found that SNPs known to be associated with serum FAs in the FADS1/2/3 region were also associated with breast milk FA composition (experiment-wise significance threshold 4.2×10−9). Hypothesis-neutral comparison of the 33 fractions showed that the most significant genetic association at the FADS1/2/3 locus was with fraction of arachidonic acid (AA) at SNP rs174556, with a very large per major allele effect size of 17% higher breast milk AA level. There was no evidence of independent association at FADS1/2/3 with any other FA or SNP after conditioning on AA and rs174556. We also found novel significant experiment-wise SNP associations with: polyunsaturated fatty acid (PUFA) 6/PUFA3 ratio (sorting nexin 29), eicosenoic (intergenic) and capric (component of oligomeric Golgi complex 3) acids; and six additional loci at genomewide significance (<5×10−8).

Conclusions AA is the primary FA in breast milk influenced by genetic variation at the FADS1/2/3 locus, extending the potential phenotypes under genetic selection to include breast milk composition, thereby possibly affecting infant growth or cognition. Breast milk FA composition is influenced by maternal genetics in addition to diet and body composition.

  • breast milk
  • fatty acids
  • selection
  • fatty acid desaturase
  • genomewide association

This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1136/jmedgenet-2017-105134

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    Footnotes

    • JCM and UN are joint first authors.

    • Contributors JCM conceptualised the study, performed statistical genetic analyses and wrote the paper. UN contributed to paper drafts. UN, ERC, DZ and SA performed data curation, interpretation and analysis. AJM supervised genotyping and quality control. WAPJ, ASGF, RH and BDK administered the study cohort research, obtained funding and reviewed the paper. MA and TA oversaw the study clinical operations and data collection. TC performed GWAS genotyping quality control analysis.

    • Funding This work was supported by the Bill and Melinda Gates Foundation (OPP1017093 and OPP1100514 to WAPJ), National Institutes of Health (AI043596 to WAPJ) and the Wellcome Trust (106289/Z/14/Z Clinical Research Training Grant to AJM and 098051 Sanger Institute Core Funding Grant).

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval Ethical Review Committee for human subjects protection and Research Review Committee for scientific merit at the International Centre for Diarrhoeal Diseases Research, Bangladesh (ICDDR,B) and the Institutional Review Boards at the University of Virginia and University of Vermont.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement The authors are happy to assist with reasonable efforts to replicate the results in this manuscript. The authors are willing to share a limited number of individual SNP summary results from these analyses that are not present in the manuscript or supplementary tables but due to identifiability concerns, complete GWAS summary statistics will require IRB approval and a data use agreement. Submission to dbGaP is in process for the PROVIDE study genotype data, accession phs001478. Other requests for individual level genetic or phenotypic data will require IRB approval and a data use agreement for a research proposal that is consistent with the consents of the individual studies.