Robert A. Philibert

Bio: Robert A. Philibert is an academic researcher from University of Iowa. The author has contributed to research in topics: DNA methylation & Epigenetics. The author has an hindex of 46, co-authored 193 publications receiving 7466 citations. Previous affiliations of Robert A. Philibert include University of Konstanz & National Institutes of Health.

The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies

Abstract: Serotonin Transporter (5HTTor SLC6A4) mRNA transcription is regulated by both genetic and epigenetic mechanisms. Unfortunately, despite intense scrutiny, the exact identity and contribution of each of these regulatory mechanisms, and their relationship to behavioral illness remain unknown. This lack of knowledge is critical because alterations in SLC6A4 function are posited to be central to a wide variety of CNS disorders. In order to address this shortcoming, we quantified 5HTTLPR genotype, SLC6A4 mRNA production and CpG methylation using biomaterial from 192 lymphoblast cell lines derived from subjects who participated in the latest wave of the Iowa Adoption Studies. We then analyzed the resulting data with respect to clinical characteristics. We confirmed prior findings that the short (s) 5HTTLPR allele is associated with lower amounts of mRNA transcription, but there was no significant effect of the “Long G” allele on mRNA transcription. We also found that CpG methylation was higher (P< 0.0008) and mRNA production (P< 0.0001) was lower in females as compared to males. Those subjects with a lifetime history of Alcohol Dependence had higher levels of SLC6A4 mRNA. There was a trend for an association of increased overall methylation with lifetime history of major depression. Finally, we confirm our prior findings that the exact levels of 5HTT mRNA expression are dependent on how it is measured. We conclude that both genetic variation and epigenetic modifications contribute to the regulation of SLC6A4 function and that more in-depth studies of the molecular mechanisms controlling gene activity and the relationship of these mechanisms to behavioral illness are indicated.

Interplay of Genes and Early Mother-Child Relationship in the Development of Self-Regulation from Toddler to Preschool Age

Abstract: Background: A broad capacity for deliberate self‐regulation plays a key role in emotion regulation. This longitudinal investigation from infancy to preschool age examines genotype by environment (G × E) interaction in the development of self‐regulation, using molecular measures of children’s genotypes and observed measures of the quality of early mother–child relationship, as reflected in attachment organization in infancy. Methods: In 89 children, we assessed the polymorphism in the serotonin transporter gene (5‐HTTLPR, ss/sl vs. ll allele status), security of attachment to mothers at 15 months in the Strange Situation, and children’s ability for self‐regulation at 25, 38, and 52 months, using behavioral batteries of tasks that called for deliberately suppressing a dominant response and performing instead a sub‐dominant response. Results: There was a robust G × E interaction between genetic risk and the quality of early relationship. Among children who carried a short 5‐HTTLPR allele (ss/sl ), those who were insecurely attached developed poor regulatory capacities, but those who were securely attached developed as good regulatory capacities as children who were homozygotic for the long allele (ll ). There was no effect of security for ll homozygotes. Conclusions: Those findings, consistent with diathesis‐stress model, bridge research on self‐regulation in typically developing children with research on non‐human primates and research on psychopathology. They also indicate that a secure attachment relationship can serve as a protective factor in the presence of risk conferred by a genotype.

Coordinated Changes in AHRR Methylation in Lymphoblasts and Pulmonary Macrophages from Smokers

Abstract: Smoking is associated with a wide variety of adverse health outcomes including cancer, chronic obstructive pulmonary disease, diabetes, depression and heart disease. Unfortunately, the molecular mechanisms through which these effects are conveyed are not clearly understood. To examine the potential role of epigenetic factors in these processes, we examined the relationship of smoking to genome wide methylation and gene expression using biomaterial from two independent samples, lymphoblast DNA and RNA (n=119) and lung alveolar macrophage DNA (n=19). We found that in both samples current smoking status was associated with significant changes in DNA methylation, in particular at the aryl hydrocarbon receptor repressor (AHRR), a known tumor suppressor. Both baseline DNA methylation and smoker associated DNA methylation signatures at AHRR were highly correlated (r=0.94 and 0.45, respectively). DNA methylation at the most differentially methylated AHRR CpG residue in both samples, cg0557592, was significantly associated with AHRR gene expression. Pathway analysis of lymphoblast data (genes with most significant methylation changes) demonstrated enrichment in protein kinase C pathways and in TGF beta signaling pathways. For alveolar macrophages, pathway analysis demonstrated alterations in inflammation-related processes. We conclude that smoking is associated with functionally significant genome wide changes in DNA methylation in both lymphoblasts and pulmonary macrophages and that further integrated investigations of these epigenetic effects of smoking on carcinogenesis and other related co-morbidities are indicated.

Methylation at SLC6A4 is linked to Family History of Child Abuse: An Examination of the Iowa Adoptee Sample

Abstract: In this letter we describe novel, preliminary work, examining a possible mechanism of the Gene-environment interactions thought to moderate the response of individuals to stressful life events. The molecular mechanisms through which this moderation may be accomplished are currently unknown but some have suggested DNA methylation (Lui and others, 1997; McGowan and others 2009). In order to test this hypothesis, we analyzed the relationship of child abuse to methylation of cytosine residues in the promoter region of the serotonin transporter gene in DNA from 96 male and 96 female subjects from the Iowa Adoptee Studies using a principal components analysis. The results from this preliminary work suggest a lasting effect of child abuse on overall methylation levels in both males and females.

Beyond Diathesis Stress: Differential Susceptibility to Environmental Influences.

Abstract: Evolutionary-biological reasoning suggests that individuals should be differentially susceptible to environmental influences, with some people being not just more vulnerable than others to the negative effects of adversity, as the prevailing diathesis-stress view of psychopathology (and of many environmental influences) maintains, but also disproportionately susceptible to the beneficial effects of supportive and enriching experiences (or just the absence of adversity). Evidence consistent with the proposition that individuals differ in plasticity is reviewed. The authors document multiple instances in which (a) phenotypic temperamental characteristics, (b) endophenotypic attributes, and (c) specific genes function less like “vulnerability factors” and more like “plasticity factors,” thereby rendering some individuals more malleable or susceptible than others to both negative and positive environmental influences. Discussion focuses upon limits of the evidence, statistical criteria for distinguishing differential susceptibility from diathesis stress, potential mechanisms of influence, and unknowns in the differentialsusceptibility equation.