DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition

Cyril J Peter; Laura K Fischer; Marija Kundakovic; Paras Garg; Mira Jakovcevski; Aslihan Dincer; Ana C Amaral; Edward I Ginns; Marzena Galdzicka; Cyralene P Bryce; Chana Ratner; Deborah P Waber; David Mokler; Gayle Medford; Frances A Champagne; Douglas L Rosene; Jill A McGaughy; Andrew J Sharp; Janina R Galler; Schahram Akbarian

doi:10.1016/j.biopsych.2016.03.2100

DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition

Biol Psychiatry. 2016 Nov 15;80(10):765-774. doi: 10.1016/j.biopsych.2016.03.2100. Epub 2016 Mar 26.

Authors

Cyril J Peter¹, Laura K Fischer², Marija Kundakovic¹, Paras Garg³, Mira Jakovcevski⁴, Aslihan Dincer⁵, Ana C Amaral⁶, Edward I Ginns⁷, Marzena Galdzicka⁸, Cyralene P Bryce⁹, Chana Ratner¹, Deborah P Waber¹⁰, David Mokler¹¹, Gayle Medford⁹, Frances A Champagne¹², Douglas L Rosene¹³, Jill A McGaughy¹⁴, Andrew J Sharp³, Janina R Galler², Schahram Akbarian¹⁵

Affiliations

¹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.
² The Chester M. Pierce, MD Division of Global Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
³ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
⁴ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Max Planck Institute for Psychiatry, Munich, Germany.
⁵ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
⁶ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
⁷ Department of Psychiatry, University of Massachusetts Medical School, Shrewsbury, Massachusetts; Department of Neurology, University of Massachusetts Medical School, Shrewsbury, Massachusetts; Department of Clinical Pathology, University of Massachusetts Medical School, Shrewsbury, Massachusetts.
⁸ Department of Pathology, University of Massachusetts Medical School, Shrewsbury, Massachusetts.
⁹ Barbados Nutrition Study, Bridgetown, Barbados.
¹⁰ Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
¹¹ Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, Maine.
¹² Department of Psychology, Columbia University, New York, New York.
¹³ Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts.
¹⁴ Department of Psychology, University of New Hampshire, Durham, New Hampshire.
¹⁵ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: schahram.akbarian@mssm.edu.

Abstract

Background: Early childhood malnutrition affects 113 million children worldwide, impacting health and increasing vulnerability for cognitive and behavioral disorders later in life. Molecular signatures after childhood malnutrition, including the potential for intergenerational transmission, remain unexplored.

Methods: We surveyed blood DNA methylomes (~483,000 individual CpG sites) in 168 subjects across two generations, including 50 generation 1 individuals hospitalized during the first year of life for moderate to severe protein-energy malnutrition, then followed up to 48 years in the Barbados Nutrition Study. Attention deficits and cognitive performance were evaluated with the Connors Adult Attention Rating Scale and Wechsler Abbreviated Scale of Intelligence. Expression of nutrition-sensitive genes was explored by quantitative reverse transcriptase polymerase chain reaction in rat prefrontal cortex.

Results: We identified 134 nutrition-sensitive, differentially methylated genomic regions, with most (87%) specific for generation 1. Multiple neuropsychiatric risk genes, including COMT, IFNG, MIR200B, SYNGAP1, and VIPR2 showed associations of specific methyl-CpGs with attention and IQ. IFNG expression was decreased in prefrontal cortex of rats showing attention deficits after developmental malnutrition.

Conclusions: Early childhood malnutrition entails long-lasting epigenetic signatures associated with liability for attention and cognition, and limited potential for intergenerational transmission.

Keywords: Attention deficits; Childhood malnutrition; Cognition; DNA methylation; Epigenetics; Prefrontal cortex.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Animals
Attention Deficit Disorder with Hyperactivity / etiology*
Attention Deficit Disorder with Hyperactivity / genetics
Barbados
Behavior, Animal*
Cognitive Dysfunction / etiology*
Cognitive Dysfunction / genetics
DNA Methylation* / genetics
Disease Models, Animal
Epigenesis, Genetic* / genetics
Follow-Up Studies
Humans
Infant
Middle Aged
Nutrition Surveys
Prefrontal Cortex / metabolism*
Protein-Energy Malnutrition / complications*
Protein-Energy Malnutrition / genetics
Rats
Young Adult

Abstract

Publication types

MeSH terms

Grants and funding