Tuesday, February 03, 2015


"What should I do to be saved?" is the religious version of the survival question.  Many families address the issue through moral and political assumptions, which are the cultural issues that also control religious allegiance.  If their members don't conform to this complex, they are blamed, excluded, and sometimes denied existence.  Survival of the individual is thus pitted against survival of the group.  If you think this sounds like the plot of "Game of Thrones," that's because it is.  But it's also what happens everywhere and in my own family.

New genetic and epigenetic research information being studied by the NIMH and the British Psychological Society and reconciled with clinical work is too new to make recommendations.  But it is certainly suggestive and possibly useful for specific individuals.  


Recent genome-wide studies revealing overlap in genetic risk that cuts across mental disorders hinted at shared biological processes, such as the workings of certain ion channels, but didn’t systematically focus on these. The PGC Network and Pathway Analysis Subgroup analyzed genome-wide data from more than 60,000 people. Using a new statistical technique called “genetic pathway analysis,” they pinpointed processes through which risk genes cause illness across diagnostic categories.

It turned out that disorders that share a typical age-of-onset, with symptoms first appearing in young adulthood , also shared the same risk gene pathways.  Genes that confer risk for schizophrenia, bipolar disorder, and depression most strongly work through pathways involved in the process of histone methylation, an epigenetic  mechanism that regulates the switching on-or-off of genes in response to environment and experience. Disruption in these pathways prenatally could adversely affect brain development, suggest the researchers.

Risk genes also were found to work via pathways involved in the communication between brain cells, and through effects on the immune system – which other lines of evidence have recently implicated in susceptibility to psychological stress and mood disorders. Additionally, the results suggested that genetic effects on histone methylation appeared to play a more prominent role in bipolar disorder, while effects on neuronal communications may more strongly impact schizophrenia.

National Institutes of Health-funded researchers discovered that people with disorders traditionally thought to be distinct – autism, ADHD, bipolar disorder, major depression and schizophrenia – were more likely to have suspect genetic variation at the same four chromosomal sites. These included risk versions of two genes that regulate the flow of calcium into cells.

Prior to the study, researchers had turned up evidence of shared genetic risk factors for pairs of disorders, such as schizophenia and bipolar disorder, autism and schizophrenia and depression and bipolar disorder. Such evidence of overlap at the genetic level has blurred the boundaries of traditional diagnostic categories and given rise to research domain criteria, or RDoC, an NIMH initiative to develop new ways of classifying psychopathology for research based on neuroscience and genetics as well as observed behavior.
To learn more, the consortium researchers analyzed the five key disorders as if they were the same illness. They screened for evidence of illness-associated genetic variation across the genomes of 33,332 patients with all five disorders and 27,888 controls, drawing on samples from previous consortium mega-analyses.

For the first time, specific variations significantly associated with all five disorders were among several suspect genomic sites that turned up. These included variation in two genes that code for the cellular machinery for regulating the flow of calcium into neurons. Variation in one of these, called CACNA1C, which had previously been implicated in susceptibility to bipolar disorder, schizophrenia and major depression, is known to impact brain circuitry involved in emotion, thinking, attention and memory – functions disrupted in mental illnesses. Variation in another calcium channel gene, called CACNB2, was also linked to the disorders.

Alterations in calcium-channel signaling could represent a fundamental mechanism contributing to a broad vulnerability to psychopathology, suggest the researchers.
They also discovered illness-linked variation for all five disorders in certain regions of chromosomes 3 and 10. Each of these sites spans several genes, and the specific causal factors within them remain elusive. However, one region, called 3p21, which produced the strongest signal of illness association, harbors suspect variations identified in previous genome-wide studies of bipolar disorder and schizophrenia.


I’m responding so strongly to this point of view because members of my family have suffered from what is probably genetic or epigenetic glitches that originally have been triggered by the historical impacts of things like famine, sequential mothering due to childbirth deaths, radical culture shift possibly due to migration, world epidemic, paternal presence shift due to economics (farms to cities).  In some ways they have suffered more because of the response to genetic code than because of the actual code problems.  "Guilt" and "Shame" are meant to drive people towards success, but often simply stamp in dysfunction harder.

Histone methylation is a system that can turn genes on and off.  If genes are like the keys in a piano, methylation can force the player to play with missing keys or double keys.  "In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes." (As nearly as I can tell, histones have nothing to do with histamines, which are connected somehow to allergies.  There are some people who will claim that something like alcoholism and other addictions are essentially allergies.  Others feel that some mental conditions are produced by autoallergies.)

Also, these difficulties seem always to affect women more than men, which is probably related to the “extra” leg on the female chromosome that makes it an X instead of a Y.  Some genetic code is on that leg and can compensate for missing genes.  But it may be an advantage not to have some genes that are on that missing leg -- perhaps about something like menstruation -- so one can never expect a good/bad binary sorting, as people always want.  Such things are just turns in the labyrinth.

Looking at life-outcomes in my family, my mother’s genetic stream is quite different from my father’s, though both are mostly Scots/Irish.  Each has characteristic distinctions, but they converge in having alcoholic uncles in every generation and quiet, withdrawing women who were good mothers but dependent on husbands.  Economic situations affected success, of course.  Homesteading and Economic Depression.

No comments: