In the September issue of the American Journal of Psychiatry, researchers report a series of studies that suggest a strong association between one particular genetic variation and manic symptoms. (Studies in humans and mice implicate neurocan in the etiology of mania. Miró X, Meier S, Dreisow ML, Frank J, Strohmaier J, Breuer R, Schmäl C, Albayram O, Pardo-Olmedilla MT, Mühleisen TW, Degenhardt FA, Mattheisen M, Reinhard I, Bilkei-Gorzo A, Cichon S, Seidenbecher C, Rietschel M, Nöthen MM, Zimmer A. Am J Psychiatry, 2012 Sep 1;169(9):982-90.)

Given all the activity and advances in genetic research, you might expect researchers to have mapped the entire human genome by now and identified the gene or genes responsible for bipolar disorder and other diseases that appear to have a genetic component. Obviously, that hasn’t happened. The best that researchers seem to have come up with are associations of certain gene variations with bipolar – hardly the smoking gun we would hope for.

Even the researchers seem to be getting a little discouraged, as is evident in a two articles I have recently come across. The first, published in the April 2011 edition of the American Journal of Psychiatry is entitled “After GWAS: Searching for Genetic Risk for Schizophrenia and Bipolar Disorder,” (by Elliot S. Gershon, Ney Alliey-Rodriguez, and Chunyu Liu). In their abstract, the authors explain:

Ten years ago it was widely expected that the genetic basis of common disease would be resolved by genome-wide association studies (GWAS), large-scale studies in which the entire genome is covered by genetic markers. However, the bulk of heritable variance remains unexplained.

Psych Central’s Senior News Editor Rick Nauert recently posted a piece entitled “Genetic Variant Heightens Risk for Bipolar Disorder.” In it, he calls attention to a recent study published in the American Journal of Human Genetics that’s “based on a relatively new technique for the study of the genetics of bipolar disorder” termed genome-wide association studies (GWAS).

We invite you to check out the post, especially if you’re interested in keeping up on the latest breakthroughs in identifying the genetic component of bipolar disorder. Although it may be years before these genetic studies translate into any sort of gene therapy, if that’s even possible, they deliver an immediate benefit in three important ways:

Researchers in Germany may have come closer to confirming one of the possible genetic components that contribute to a vulnerability to bipolar disorder. For some time, we have known two things about bipolar disorder:

• It’s a brain illness, a neurological disorder.
• It has a strong genetic component.

The unknown, until now, was the link between the genetic component and the actual neural abnormalities. Relatively recently, several studies have implicated a variant on chromosome 12, the CACNA1C gene, as increasing the risk for bipolar disorder. So researchers wanted to find out whether this gene variant could be traced to a particular region of the brain.

Researchers at Johns Hopkins University School of Medicine have published a study entitled “Chronic Corticosterone Exposure Increases Expression and Decreases Deoxyribonucleic Acid Methylation of Fkbp5 in Mice,” Endocrinology, September 2010, in which they claim to have identified a possible epigenetic cause of depression and other mood disorders, including bipolar disorder. For a more layman’s account of the study and its conclusions, I recommend the Johns Hopkins press release entitled “Chronic Stress May Cause Long-Lasting Epigenetic Changes.”

The prefix epi- means outside, above, over, or on top of. The term epigenetic refers to factors outside the fundamental gene structure that affect a gene’s expression. In this study, researchers examined the effects of a common stress hormone on a gene that has been linked to mood disorders and found that “… long-term exposure to a common stress hormone may leave a lasting mark on the genome and influence how genes that control mood and behavior are expressed.”

Purple Tablets Asks…

I’m a female of child-bearing age… who has been diagnosed as Bipolar II. The message that the different doctors have given me so far has been “don’t get pregnant.” (In fact, one offended me so much with how she delivered this message that I cancelled my follow-up appointment and got a new psychiatrist!)

Results of a recent study published in the September 30, 2008 issue of the Proceedings of the National Academy of Sciences, suggest that a relatively common gene mutation may protect people from ever developing bipolar disorder. The study, entitled “A common variant in the 3′UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder,” suggests that a missing section of DNA in GRIK4 gene provides the protection.

A study published in this month’s General Archives of Psychiatry entitled “Advancing Paternal Age and Bipolar Disorder,” reports that children of older fathers have a higher risk of developing bipolar disorder than children of younger fathers. This is a large study, and the data are quite strong. Fathers age 40 and older show some increased risk of having a child with bipolar disorder, but the risk really grows with fathers ages 55 and older.

Recently, the NIMH (National Institute of Mental Health) distributed a press release entitled “Largest Study of Its Kind Implicates Gene Abnormalities in Bipolar Disorder.” According to the press release, this “largest genetic analysis of its kind to date for bipolar disorder has implicated machinery involved in the balance of sodium and calcium in brain cells.” As the press release points out, no single gene has been identified as the “bipolar gene.” Researchers generally agree that multiple genes contribute to make an individual more susceptible to the eventual onset of bipolar disorder.

For more about bipolar disorder genetics and heredity, check out Dr. Fink’s two-part series – “Bipolar Disorder & Heredity: The Genetic Link.”

In Part I of this two-part series, we examined the role that genetics likely plays in the onset of bipolar disorder and learned that genetics contributes up to 80%, with environmental factors contributing about 20% or more. (This means that if someone has bipolar disorder, the cause of it is 75-80% due to genetics. It does not mean an individual in a family with a history of bipolar has a 75-80% chance of developing it. See Part I for statistics on the inheritability of bipolar.)

It appears that for most people there needs to be some environmental factors that “turn on” the genes responsible for one’s vulnerability to bipolar disorder. Many of these environmental triggers may occur early in life and may include things such as: