Ankyrin-3 as a molecular marker of early-life stress and vulnerability to psychiatric disorders.
Exposure to early-life stress (ELS) may heighten the risk for psychopathology at adulthood. Here, in order to identify common genes that may keep the memory of ELS through changes in their methylation status, we intersected methylome analyses performed in different tissues and time points in rats, non-human primates and humans, all characterized by ELS. We identified Ankyrin-3 (Ank3), a scaffolding protein with a strong genetic association for psychiatric disorders, as a gene persistently affected by stress exposure. In rats, Ank3 methylation and mRNA changes displayed a specific temporal profile during the postnatal development. Moreover, exposure to prenatal stress altered the interaction of ankyrin-G, the protein encoded by Ank3 enriched in the post-synaptic compartment, with PSD95. Notably, to model in humans a gene by early stress interplay on brain phenotypes during cognitive performance, we demonstrated an interaction between functional variation in Ank3 gene and obstetric complications on working memory in healthy adult subjects. Our data suggest that alterations of Ank3 expression and function may contribute to the effects of ELS on the development of psychiatric disorders.
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
A
A
Luoni
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
R
R
Massart
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.|Department of Psychiatry and Psychotherapy, University of Tuebingen, Tuebingen, Germany.
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V
Nieratschker
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.|Sackler Institute for Epigenetics and Psychobiology, McGill University, Montreal, QC, Canada.
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Z
Nemoda
Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
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0000-0003-0878-1131
G
Blasi
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
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M
Gilles
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
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SH
Witt
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.|Sackler Institute for Epigenetics and Psychobiology, McGill University, Montreal, QC, Canada.|McGill Centre for Bioinformatics, McGill University, Montreal, QC, Canada.
M J
MJ
Suderman
Laboratory of Comparative Ethology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
S J
SJ
Suomi
Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
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A
Porcelli
Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
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G
Rizzo
Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
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L
Fazio
Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
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S
Torretta
Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
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A
Rampino
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
A
A
Berry
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
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P
Gass
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
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F
Cirulli
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
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M
Rietschel
Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
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A
Bertolino
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
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M
Deuschle
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.|Sackler Institute for Epigenetics and Psychobiology, McGill University, Montreal, QC, Canada.
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M
Szyf
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
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MA
Riva
D000818:Animals; D017487:Ankyrins / Q000235:genetics*; D001714:Bipolar Disorder / Q000235:genetics; D015331:Cohort Studies; D019175:DNA Methylation; D004195:Disease Models, Animal; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D007231:Infant, Newborn; D008016:Life Change Events; D008253:Macaca mulatta; D008297:Male; D008570:Memory, Short-Term; D001523:Mental Disorders / Q000235:genetics*; D010641:Phenotype; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D012559:Schizophrenia / Q000235:genetics
C490613:ANK3 protein, human; D017487:Ankyrins; D005819:Genetic Markers