Humans are not fruit flies and the brain is not a simple organ, so depression and bipolar disorder are hardly going to yield their genetic secrets easily. The quest for the genetic cause or causes of depression and bipolar disorder represents a virtual scientific Boulevard of Broken Dreams thus far, but the prospect of hitting paydirt always lies around the corner. A commentary by different Johns Hopkins authors on the website of the NIH National Center for Biotechnology Information provides a good overview of what we know and don't know. Among the highlights:

The role of genes in affective disorders is underscored by the concordance between identical twins at 57 percent and fraternal twins at 14 percent.
A 1993 study of 34 families with bipolar found the second generation experienced onset 8.9 to 13.5 years earlier and illness 1.8 to 3.4 times more severe than their parents. Other experts, however, dispute this finding.
A 1994 study found 71 affected individuals responded to lithium treatment and 50 did not. Nearly four percent of the first-degree relatives of the lithium responders had bipolar but not so for the relatives of the nonresponders.
A 1995 study of 31 families found an increased risk of bipolar both to mothers and through the mother line, with the fathers failing to transmit symptoms to their offspring, corroborating earlier studies. A 1999 study suggested the cause may be "mitochondrial DNA mutations." A different 1995 study, however, found paternal pedigrees for loci on chromosome 18p and 18q, which represent prime suspect genes.
A number of studies suggests one or more regions of the X chromosome are suspect, with linkages to color-blindness and G6PD deficiency (pertaining to a red cell enzyme). A 1982 study speculated a third of those with bipolar carried the X-linked gene. Other findings question these results.
A "haplotype" is a cluster of DNA thought to be inherited as a unit. HLA are proteins located in white blood cells and other tissue. A number of studies of affected families has found sharing of HLA haplotypes higher than normal. One study suggests the HLA effect may be greater for unipolar depression and more apparent in families with few affected members.
A 1987 study of the Old Order Amish purportedly localized "a dominant [bipolar] gene" on the tip of the short arm of chromosome 11. Later studies, however, ruled out this link. More recent studies of the Amish have identified suspects on chromosomes 6, 13, 15, and 18. A 1996 study, however, cast doubt on these findings. A 1998 study of the Old Amish found strong evidence for linkage to mental health wellness on chromosome 4p.
Other studies on genetically isolated populations and their suspect genes include the Faroe Islands (chromosome 12q24), the Central Valley of Costa Rica (11p, 18p,18q), and Iceland (11q).
Studies of bipolar families point to a number of suspects: 1p21-p22, 3p21, 3q27, 5p15, 5q32, 9p22.3-p21.1, 9q34, 10q, 12q23-q24, 13q31-q34, 14q24.1-q32.12, 17q21.3, 18p, 18q, 21q22.3, 22q12, 21q22, and 22q13.2. Chromosomes 10q, 13q, and 22q have also been implicated in schizophrenia.

Challenging Assumptions About Bipolar Disorder and Depression

In the meantime, a series of recent Johns Hopkins studies challenges our assumptions about bipolar disorder, namely: 1) psychotic bipolar disorder may be a genetic subtype of bipolar disorder, possibly sharing some of the same chromosomes as schizophrenia, a thought that would have been apostasy until recently; 2) bipolar II may be genetically distinct from bipolar I, with individuals in bipolar II families showing an affinity to chromosome 18q21; 3) a possible link between bipolar and panic disorder, which a JAMA editorial called "striking."

What do these findings tell us? Bipolar disorder is a complex illness probably caused by multiple genes, says Raymond DePaulo MD, co-author of the three Johns Hopkins studies and chair of that university’s Department of Psychiatry and Behavioral Sciences. It may take any three of ten genes, for instance, to cause bipolar disorder. Say one in five people carried any one of these three genes, then rough mathematics (1/5 x 1/5 x 1/5) would yield 1/125, representing approximately the one percent of the population that has bipolar disorder.

Right now, research is at the statistical association stage, with expert consensus centering on anywhere from six to ten chromosomal regions. But that hardly constitutes evidence. "We have to show biologically what the gene does, what the mutation does, to cause the disease" Dr DePaulo told this writer.

Or, in the words of David Weinberger MD, Chief of the Clinical Brain Disorders Branch at the NIMH, speaking at the 2003 American Psychiatric Association’s annual meeting, "how we get there from here," from identifying the gene to its cellular function to its role in the systems in the brain to its affect on behavior. He pointed to Ahmad Hariri PhD et al's 2002 ground-breaking study of what needs to be done. In that NIMH study, brain scans revealed a greater amygdala response (associated with fear) in individuals with the short allele (variant) of the serotonin transporter gene SLC6A4 (responsible for reuptake of serotonin) when asked to look at images of faces, which could well be the first study linking genes to emotions in humans.

In 2003, a team of researchers at the University of Wisconsin and King's College (London) investigating the same gene reported that in a large population, those with the short allele who had been subjected to at least four recent life stresses (such as employment, finances, housing, health, and relationships) were twice as likely to become depressed.

The authors of that study argued that genetic research trying to link genes to illness has not proven fruitful for complex psychiatric disorders. Instead, they have pursued a different line of enquiry based on the interactions between genes and environment, which assumes some genetic variants are more resistant to environmental stressors than others and which can be uncovered in part by measuring the effects of these stressors.

Back to Watson and Crick

Meanwhile, cast your mind back a half-century:

"We wish to suggest a structure for the salt of deoxyribose nucleicacid (DNA)," began a one-page paper published in Nature 50 years ago. With what can only be called hyperbolic understatement, the article went on to say: "This structure has novel features which are ofconsiderable biological interest." The authors were James Watson and Francis Crick, the structure was the double helix, and biological science would never be the same.

April 2003's American Journal of Psychiatry commemorates the fiftieth anniversary of the publication of Watson and Crick's groundbreaking paper, with several articles devoted to "the genomic era," which, according to an editorial, "is about much more than 'findinggenes.' It is about understanding how they get turned on, orturned off. It is about examining the complex interactions betweengenes and the huge array of nongenetic factors that influencetheir effects. It is about our capacity as scientists and cliniciansto improve diagnosis, treatment, and, ultimately, prevention."

So far, the literature concerning genes and the brain has focused on less than one percent of the genome, representing a mere 300 or so genes. Yet our research on mice tells us 55 percent of our genes (roughly 16,500 genes) are expressed in the brain. According to Thomas Insel MD and Francis Collins MD, PhD, directors of the NIMH and Human Genome Project, respectively: "We have a treasure trove of new genesto explore, including many that may prove more important thanthe few neurotransmitters and intracellular signaling moleculesthat have been studied so intensively these past 50 years."

Thinking Outside the Box to Endophenotype

The hunt for depression and bipolar genes can be likened to searching for pieces of hay in a haystack. There is no one gene that is likely to stand out. Instead, we're searching for what are probably common and fairly humdrum mutations to what may be more than ten genes, each with a modest effect. The search is further confounded by the fact that unlike say diabetes, a mood disorder leaves no discernible biological footprint equivalent to blood glucose. Not surprisingly, our efforts to link social wallflower genes to phantom footprint symptoms - or "phenotype" - by studying twins and families and isolated populations have been disappointing, yielding at best some possible suspects.

Accordingly, researchers are thinking outside the DSM box to the underlying biology of "endophenotype," such as sleep and circadian rhythms and appetite regulation. Intriguingly, some of the suspect genes we have identified may be responsible for more than one illness, raising such possibilities as schizophrenia and bipolar patients sharing some of the same psychosis genes.

The following example from schizophrenia gene research illustrates endophenotype at work:

At the 2003 APA annual meeting, Robert Freedman MD of the University of Colorado stressed that "the DSM-IV was not designed with human gene function in mind and genes do not encode for psychopathology." Instead, he went on to say, "genes encode simple molecules in cells that alter cell function and brain information processing."

Dr Freedman has been exploring a link between "sensory gating disturbance" and why people with schizophrenia crave nicotine. A normal person, for instance can tune out the second of two repetitive sounds. Many people with schizophrenia, however, cannot, and so have great trouble concentrating. Dr Freedman’s team found that auditory gating is modulated by the alpha7 nicotinic receptor, with linkage to chromosome 15q14. Alpha7 is reduced in the hippocampi of patients with schizophrenia. In one study, patients on nicotine lost their response to the second sound. Nicotine, Dr Freedman said, can serve as a model for future treatment, but instead of making a toxin we can make an agonist.

Eventually, we may be able redefine mental illness according to "genotype" that would render the DSM obsolete. As Insel and Collins conclude:

"Students of the history of psychiatry looking backfrom the Watson and Crick centennial in 2053 may wonder howwe could have been so interested in serotonin and dopamine in2003 when many hundreds of more important factors remained tobe found.^"

(Also see Sense, Nonsense, and Antisense.)

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Updated June 14, 2004

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Raymond DePaulo: "Finding the first gene is going to take luck."