Methylation Matters: Interaction Between Methylation Density and Serotonin Transporter Genotype Predicts Unresolved Loss or Trauma


      Do genetic or epigenetic factors play a role in making some individuals more vulnerable than others to loss of attachment figures or other traumatic experiences?


      DNA was obtained from growth phase entrained Epstein-Barr Virus (EBV) transformed lymphoblast cell lines from 143 adopted participants. Genotype of the serotonin transporter linked polymorphic region (5HTTLPR) was determined, and methylation ratios for each of the C-phosphate-G (CpG) residues were assessed using quantitative mass spectroscopy. Unresolved loss or trauma was established using the Berkeley Adult Attachment Interview.


      Higher levels of methylation of the 5HTT promoter associated CpG island were associated with increased risk of unresolved responses to loss or other trauma in carriers of the usually protective 5HTTLPR ll variant. The ss variant of 5HTTLPR predicted more unresolved loss or trauma, but only in case of lower levels of methylation. Higher levels of methylation of the ss variant were associated with less unresolved loss or other trauma.


      Associations between 5HTTLPR polymorphisms and psychological problems are significantly altered by environmentally induced methylation patterns. Methylation may serve as the interface between adverse environment and the developing organism.

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        • Pierrehumbert B.
        • Torrisi R.
        • Glatz N.
        • Dimitrova N.
        • Heinrichs M.
        • Halfon O.
        The influence of attachment on perceived stress and cortisol response to acute stress in woman sexually abused in childhood or adolescence.
        Psychoneuroendocrinology. 2009; 34: 924-938
        • Sagi-Schwartz A.
        • Van IJzendoorn M.H.
        • Grossman K.E.
        • Joels T.
        • Grossman K.
        • Scharf M.
        • et al.
        Attachment and traumatic stress in female Holocaust child survivors and their daughters.
        Am J Psychiatry. 2003; 160: 1086-1092
        • Hesse E.
        The adult attachment interview: Protocol, method of analysis, and empirical studies.
        in: Cassidy J. Shaver P.R. Handbook of Attachment Theory, Research, and Clinical Applications. 2nd ed. Guilford, New York2008: 552-598
        • Main M.
        • Kaplan N.
        • Cassidy J.
        Security in infancy, childhood and adulthood: A move to the level of representation.
        Mon Soc Res Child Dev. 1985; 50: 66-106
        • Bakermans-Kranenburg M.J.
        • van IJzendoorn M.H.
        The first ten thousand adult attachment interviews: Distributions of adult attachment representations in clinical and non-clinical groups.
        Att Human Dev. 2009; 11: 223-263
        • Bradley S.
        • Dodelzon K.
        • Sandhu H.
        • Philibert R.
        The relationship of serotonin transporter gene polymorphisms and haplotypes to mRNA transcription.
        Am J Med Genet. 2005; 136: 58-61
        • Lesch K.P.
        • Bengel D.
        • Heils A.
        • Sabol S.Z.
        • Greenberg B.D.
        • Petri S.
        • et al.
        Association of anxiety related traits with a polymorphism in the serotonin transporter gene regulatory region.
        Science. 1996; 274: 1527-1531
        • Philibert R.A.
        • Madan A.
        • Anderson A.
        • Cadoret R.
        • Packer H.
        • Sandhu H.
        Serotonin transporter mRNA levels are associated with the methylation of an upstream CpG island.
        Am J Med Genet. 2007; 144B: 101-105
        • Stoltenberg S.F.
        • Twitchell G.R.
        • Hanna G.L.
        • Cook E.H.
        • Fitgerald H.E.
        • Zucker R.A.
        • et al.
        Serotonin transporter promoter polymorphism, peripheral indexes of serotonin function, and personality measures in families with alcoholism.
        Am J Med Genet. 2002; 144B: 230-234
        • Caspi A.
        • Sugden K.
        • Moffitt T.E.
        • Taylor A.
        • Craig I.W.
        • Harrington H.
        • et al.
        Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene.
        Science. 2003; 301: 386-389
        • Kilpatrick D.G.
        • Koenen K.C.
        • Ruggiero K.J.
        • Acierno R.
        • Galea S.
        • Resnick H.S.
        • et al.
        The serotonin transporter genotype and social support and moderation of posttraumatic stress disorder and depression in hurricane-exposed adults.
        Am J Psychiatry. 2007; 164: 1693-1699
        • Munafo M.R.
        • Durrant C.
        • Lewis G.
        • Flint F.J.
        Gene × environment interaction at the serotonin transporter loci.
        Biol Psychiatry. 2009; 65: 211-219
        • Risch N.
        • Herrell R.
        • Lehner T.
        • Liang K.Y.
        • Eaves L.
        • Hoh J.
        • et al.
        Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression.
        JAMA. 2009; 301: 2462-2471
        • Uher R.
        • Mc Guffin P.
        The moderation by the serotonin transporter gene of environmental adversity in the etiology of depression: 2009 Update.
        Mol Psychiatry. 2010; 15: 18-22
        • Meaney M.J.
        Epigenetics and the biological definition of gene × environment interactions.
        Child Dev. 2010; 81: 41-79
        • Beach S.R.H.
        • Brody G.H.
        • Todorov A.A.
        • Gunter T.D.
        • Philibert R.A.
        Methylation at SLC6A4 is linked to family history of child abuse: An examination of the Iowa adoptee sample.
        Am J Med Genet B. 2010; 153B: 710-713
        • Caspers K.
        • Paradiso S.
        • Yucuis R.
        • Troutman B.
        • Arndt S.
        Association between the serotonin transporter promoter polymorphism (5-HTTLPR) and adult unresolved attachment.
        Dev Psych. 2009; 45: 64-76
        • Derogatis L.
        Brief Symptom Instrument.
        National Computer Systems, Minneapolis, MN1996
        • McGowan P.O.
        • Sasaki A.
        • D'Alessio A.C.
        • Dymov S.
        • Labonte B.
        • Szyf M.
        • et al.
        Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse.
        Nat Neurosci. 2009; 12: 342-348
        • Grafodatskaya D.
        • Choufani S.
        • Ferreira J.C.
        • Butcher D.T.
        • Lou Y.
        • Zhao C.
        • et al.
        EBV transformation and cell culturing destabilizes DNA methylation in human lymphoblastoid cell lines.
        Genomics. 2010; 95: 73-83