In November 2000, I was presenting at a conference in New York City on bipolar disorders in which Kay Redfield Jamison was the keynote speaker. The organizer of the conference, a psychoanalyst (the conference was sponsored by a psychoanalytic institute), reported a figure of 80% concordance rates between MZ twins for bipolar disorder. Jamison reported that the figure was closer to 100%. This is recorded on tape, so I am not mistaken about this. One of the purposes of the conference was to sensitize psychotherapists and psychoanalysts in New York City to the overriding role of genetics in these disorders and the need for psychopharmacological consultations for their bipolar patients. Having a background in the neuroscience of severe mental illness, I knew these reported figures were significantly inflated. To be sure about this, I spent a great deal of time researching this issue after the conference and have since contacted the organizer to point out his mistake and to clarify the complexities of neurogenetics.

Six controlled studies revealed a 50% concordance rate for MZ (monozygotic) twins who share 100% of their genome (the source for these studies is Psychiatric Genetics & Genomics edited by Peter McGuffin, Michael Owen & Irving Gottesman in 2002 for Oxford University Press). 60% would be a conservatively inflated figure. The 80% figure reported by the conference organizer was actually 79% and this applied not just to bipolar disorder but the statistic included unipolar depressed patients (this is the Danish twin study of Bertelsen et al 1977 -- the older the studies, parenthetically, the more inflated the figures -- newer studies use stricter diagnostic criteria and tend to report lower concordance rates in MZ twins for bipolar disorder). The presenter did not point out to the audience that his figure was conflating unipolar and bipolar patients and therefore was a misleading statistic. Jamison’s figure of 100% was not backed up then or now by any research study and is surprising since she is considered an expert in the field and has written an authoritative text on the subject with Fred Goodwin. Müller and Kennedy (2005-”Recent advances in genetics of bipolar disorder” in Bipolar Disorder: The Upswing in Research and Treatment edited by Colm McDonald et al for the European Foundation for Psychiatry at The Maudsley-Taylor & Francis) also reported a 50% concordance rate for MZ twins in bipolar disorder. I highly recommend this article for anyone interested in the complexities involved in this kind of research. Müller and Kennedy concluded:

“There is unequivocal evidence that genetic factors play a major role in the aetiology of BD [bipolar disorder]. More precisely, we expect that a yet unknown number of gene variants confer susceptibility to BD that will lead to exacerbation of manic or depressive episodes in conjunction with environmental factors [there is increasing evidence that sociocultural factors play a significant role in the initiation, course and outcome of bipolar disorders -- At the end of this posting I am including research on psychosocial factors reported by Johnson and Meyer (2004)] such as stress or major life events.

The search for vulnerability genes over the past 20 years has not been as successful as initially hoped. This time period has left behind many inconsistent findings and some false leads” (p.87).

Merikangas and Yu (2005-”Challenges in the genetics of bipolar disorder” in Bipolar Disorders:Mixed States, Rapid Cycling, and Atypical Forms edited by Andreas Marneros and Frederick Goodwin for Cambridge University Press) reported concordance rates for bipolar disorder in MZ twins ranging from 33% to 93% (the latter is the 1953 study by Kallman and is the most deviant report in the literature -- far exceeding any other study-yet by taking this study seriously -- and I have spoken to a researcher who worked with Kallman and the latter was reported to not be adhering to scientific principles and was allowing his bias to override diagnostic precision -- and including this study in the averaging of the research leads to an inflated concordance statistic). Again, in the research reported by Merikangas and Yu (2005) the newer studies all report lower concordance rates than the older studies. The latter researchers also reported adoption studies of bipolar patients. They concluded:

“With respect to bipolar disorder, there is little evidence for differential risk among biologic compared to adoptive relatives of adoptees with bipolar disorder” (p.287). The authors suggested that the small numbers of bipolar adoptees (i.e., less than 50) do not provide an adequate test for differentiating genetic and environmental influences.

As I pointed out in numerous papers, these studies do not control for an increasingly viewed source of significant error variance, i.e., the effects of prenatal stress which impacts in a negative way on fetal neurodevelopment, particularly affecting later affect regulation.

The effects of environmental sharing in utero is a potential and significant source of variance between MZ & DZ twins. Approximately 65% of MZ twins share a common chorion, while DZ twins never do. A consequence of this shared blood supply could be to increase the chances that environmental factors affects both MZ twins, e.g., a viral infection, maternal stress hormones (i.e., cortisol-a teratogenic high risk factor), etc. Competition for nutrition and space could potentially lead to differences in growth rates, neural development, etc. Studies need to be done comparing monochorionic and dichorionic MZ twins to help differentiate this source of error variance. Also, studies need to be done comparing psychological and social factors potentially differentiating MZ from DZ twins in order to arrive at more valid conclusions about genetic factors as a source of variance. Ainslee (1997)has examined in twins such issues as identity confusion, separation and dependency, role complementarity, and concluded that there is a “specific psychology of twinship” (p. xii). On a basic biological level, Jean-Pierre Changeux (2002) in his The Physiology of Time: Neuroscience and Human Knowledge ( Cambridge, MA: Harvard University Press), pointed out that even MZ twins have diversity in the typology of their cerebral cortex, e.g., in the planum temporale-the surface of the language area. He concluded: “...it is plain that significant variability exists in the anatomy of the brain, the typology of the cortical areas, and details of neural connections-proof that the control exercised by genes is far from absolute” (p. 188).

These studies on genetics pay little or no attention to another emerging area of significant research in medical and psychiatric disorder: epigenetics, particularly social and environmental control of gene expression. There is strong evidence for the transgenerational transmission of defenses against threats to survival through nongenomic pathways. Inducible defenses against threat can be inherited apart from information encoded in the nuclear gene. Arturas Petronis (2004) defined epigenetics:

“By definition, epigenetics refers to regulation of gene expressions that are controlled by heritable but potentially reversible changes in DNA methylation and/or chromatin structure” (p.175-in “Schizophrenia, neurodevelopment, and epigenetics” in Neurodevelopment and Schizophrenia edited by Matcheri Keshavan, James Kennedy & Robin Murray in 2004 for Cambridge University Press).

Molecular Genetics of Bipolar Disorder
Association studies investigate the relationship between disease status and a specific marker or allele across families and individuals. Most association studies investigate the prevalence of a putative disease marker among persons with the disease compared to persons without the disorder. The research in bipolar disorder has focused on such polymorphisms as 5-HTTLPR (an insertion/deletion polymorphism located in the promoter region of the serotonin transporter gene reported to affect the expression of the transporter-there exists research demonstrating social and environmental control of the expression of this gene which is ignored in current ‘genetic’ research). Other polymorphisms such as COMT (catechol-O-methyltransferase-an amino acid substitution thought to affect enzymatic activity) and a repeat polymorphism in the promoter region of a monoamine oxidase A (MAOA) gene have also been studied. Unfortunately, conflicting (i.e., nonreplication) results have been found for all three polymorphisms.

Linkage studies are based on the principle that two genes which lie in close proximity on a chromosome are transmitted to their progeny together. Linkage differs from association studies in that linkage is based on an association between genetic markers and putative genes within families, whereas association is the co-occurrence of a marker and disease at the level of the general population. Merikangas and Yu (2005), in their review of empirical studies of linkage in bipolar disorder, report that in a summary of genome-wide linkage studies of 3538 bipolar I disorder scans, no two studies conclusively implicate the same region. Because of the ambiguities in this area of research, the authors recommend a shift away from linkage and linkage-disequilibrium analysis to forward-genetic approaches. They concluded: “Ironically, the public tends to attribute far greater significance to genetic markers than has been realized for most of the complex human disorders” (pp.299-300).

The psychosocial research in bipolar disorder has been summarized in “Psychosocial predictors of symptoms” by Sheri Johnson and Björn Meyer in “Psychological Treatment of Bipolar Disorder” edited by Sheri Johnson and Robert Leahy in 2004 for The Guilford Press.

Johnson and Meyer (2004) concluded:
“...we have provided an overview of several different predictors of symptom course in people with bipolar disorder. Many variables are associated with increases in symptoms over time, including expressed emotion, negative life events, poor social support, negative cognitive styles, and personality difficulties. Many of these variables seem to exert a stronger influence on depression than mania, and it seems that many of the psychosocial variables that predict unipolar depression may influence the course of bipolar depression. Mania appears specifically influenced by sleep deprivation and increased activity within the behavioral activation system. Although the evidence is not as robust, writers over the past 100 years have suggested that manic symptoms can occasionally reflect a reaction to negative life events and cognitions. Such a reaction could reflect biological instability or a more psychological process-namely, that manic activity may be triggered as a defense against overwhelming feelings of loss or failure...In sum, psychosocial variables appear to play an important role in the exacerbation of symptoms in bipolar disorder, and positive social environments and psychological traits may help reduce the toll of this disorder” (pp.87-98).

Brian Koehler PhD
New York University
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