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Do Schizophrenia and Bipolar Disorder Share Genetic Roots?

Chromosomal Hotspot of Immunity/Gene Expression Regulation Implicated

A trio of genome-wide studies – collectively the largest to date – has pinpointed a vast array of genetic variation that cumulatively may account for at least one third of the genetic risk for schizophrenia. One of the studies traced schizophrenia and bipolar disorder, in part, to the same chromosomal neighborhoods.

"These new results recommend a fresh look at our diagnostic categories," said Thomas R. Insel, M.D., director of the National Institute of Mental Health (NIMH), part of the National Institutes of Health. "If some of the same genetic risks underlie schizophrenia and bipolar disorder, perhaps these disorders originate from some common vulnerability in brain development."

Three schizophrenia genetics research consortia, each funded in part by NIMH, report separately on their genome-wide association studies online July 1, 2009, in the journal Nature. However, the SGENE, International Schizophrenia (ISC) and Molecular Genetics of Schizophrenia (MGS) consortia shared their results - making possible meta-analyses of a combined sample totaling 8,014 cases and 19,090 controls.

All three studies implicate an area of Chromosome 6 (6p22.1), which is known to harbor genes involved in immunity and controlling how and when genes turn on and off. This hotspot of association might help to explain how environmental factors affect risk for schizophrenia. For example, there are hints of autoimmune involvement in schizophrenia, such as evidence that offspring of mothers with influenza while pregnant have a higher risk of developing the illness.

"Our study was unique in employing a new way of detecting the molecular signatures of genetic variations with very small effects on potential schizophrenia risk," explained Pamela Sklar, M.D., Ph.D., of Harvard University and the Stanley Center for Psychiatric Research, who co-led the ISC team with Harvard's Shaun Purcell, Ph.D.

"Individually, these common variants' effects do not all rise to statistical significance, but cumulatively they play a major role, accounting for at least one third – and probably much more – of disease risk," said Purcell.

Among sites showing the strongest associations with schizophrenia was a suspect area on Chromosome 22 and more than 450 variations in the suspect area on Chromosome 6. Statistical simulations confirmed that the findings could not have been accounted for by a handful of common gene variants with large effect or just rare variants. This involvement of many common gene variants suggests that schizophrenia in different people might ultimately be traceable to distinct disease processes, say the researchers.

"There was substantial overlap in the genetic risk for schizophrenia and bipolar disorder that was specific to mental disorders," added Sklar. "We saw no association between the suspect gene variants and half a dozen common non-psychiatric disorders."

Still, most of the genetic contribution to schizophrenia, which is estimated to be at least 70 percent heritable, remains unknown.

"Until this discovery, we could explain just a few percent of this contribution; now we have more than 30 percent accounted for," said Thomas Lehner, Ph.D., MPH, chief of NIMH's Genomics Research Branch. "The new findings tell us that many of these secrets have been hidden in complex neural networks, providing hints about where to look for the still elusive – and substantial – remaining genetic contribution."

The MGS consortium pinpointed an association between schizophrenia and genes in the Chromosome 6 region that code for cellular components that control when genes turn on and off. For example, one of the strongest associations was seen in the vicinity of genes for proteins called histones that slap a molecular clamp on a gene's turning on in response to the environment. Genetically rooted variation in the functioning of such regulatory mechanisms could help to explain the environmental component repeatedly implicated in schizophrenia risk.

The MGS study also found an association between schizophrenia and a genetic variation on Chromosome 1 (1p22.1) which has been implicated in multiple sclerosis, an autoimmune disorder.

"Our study results spotlight the importance not only of genes, but also the little-known DNA sequences between genes that control their expression," said Pablo Gejman, M.D., of the NorthShore University HealthSystem Research Institute, of Evanston, ILL, who led the MGS consortium team. "Advances in biotechnology, statistics, population genetics, and psychiatry, in combination with the ability to recruit large samples, made the new findings possible."

The SGENE consortium study pinpointed a site of variation in the suspect Chromosome 6 region that could implicate processes related to immunity and infection. It also found significant evidence of association with variation on Chromosomes 11 and 18 that could help account for the thinking and memory deficits of schizophrenia.

The new findings could eventually lead to multi-gene signatures or biomarkers for severe mental disorders. As more is learned about the implicated gene pathways, it may be possible to sort out what's shared by, or unique to, schizophrenia and bipolar disorder, the researchers say.

 

Schizophrenia and bipolar disorder share genetic roots that appear to be specific to serious mental disorders, and are not shared by non-psychiatric illnesses. Bars representing different study samples show that the same genetic variations that account for risk in both mental disorders account for virtually none of the risk for coronary artery disease (CAD), Crohn's disease (CD), hypertension (HT), rheumatoid arthritis (RA), or Type 1 (T1D) or Type 2 (T2D) diabetes.

Source: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Harvard University.

References

Jianxin S, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. July 1, 2009, Nature

Stefansson H, et al. Common variants conferring risk of schizophrenia. July 1, 2009, Nature

Purcell SM, et al. Common polygenic variation contributes to risk of schizophrenia that overlaps with bipolar disorder. July 1, 2009, Nature

Source: National Institute of Mental Health

Reference: Original Article

Great YouTube Video on Bipolar Disorder

Great Informational Websites Created by Dr. Speller and Dr. Korkosz:

• Stress and the Human Brain
• Early Life Stress and the Immune System
• The Facts About Major Depressive Disorder
• The Parent's Guide to Understanding Adolescent Depression

Sources: National Institute of Mental Health, Also see blogposts in Psychiatric Disorders: Bipolar

Additional Resources:

• For related articles on the Web, click on: “Sphere: Related Content” located at the bottom of this blog post.
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Dr. Jeffrey Speller

Dr. Tanya Korkosz

Psychopharmacology Associates of New England

www.psychopharmassociates.com

Do Brain Emotion Circuits Light Up When Teen Girls Size Up Peers?

What is going on in teenagers' brains as their drive for peer approval begins to eclipse their family affiliations? Brain scans of teens sizing each other up reveal an emotion circuit activating more in girls as they grow older, but not in boys. The study by Daniel Pine, M.D., of the National Institute of Mental Health (NIMH), part of National Institutes of Health, and colleagues, shows how emotion circuitry diverges in the male and female brain during a developmental stage in which girls are at increased risk for developing mood and anxiety disorders.

"During this time of heightened sensitivity to interpersonal stress and peers' perceptions, girls are becoming increasingly preoccupied with how individual peers view them, while boys tend to become more focused on their status within group pecking orders," explained Pine. "However, in the study, the prospect of interacting with peers activated brain circuitry involved in approaching others, rather than circuitry responsible for withdrawal and fear, which is associated with anxiety and depression."

Pine, Amanda Guyer, Ph.D., Eric Nelson, Ph.D., and colleagues at NIMH and Georgia State University, report on one of the first studies to reveal the workings of the teen brain in a simulated real-world social interaction, in the July, 2009 issue of the Journal Child Development.

Thirty-four psychiatrically healthy males and females, aged 9 to 17, were ostensibly participating in a study of teenagers' communications via Internet chat rooms. They were told that after an fMRI (functional magnetic resonance imaging) scan, which visualizes brain activity, they would chat online with another teen from a collaborating study site. Each participant was asked to rate his or her interest in communicating with each of 40 teens presented on a computer screen, so they could be matched with a high interest participant (see picture below).

Two weeks later, the teens viewed the same faces while in an fMRI scanner. But this time they were asked to instead rate how interested they surmised each of the other prospective chatters would be in interacting with them.

Only after they exited the scanner did they learn that, in fact, the faces were of actors, not study participants, and that there would be no Internet chat. The scenario was intended to keep the teens engaged –– maintain a high level of anticipation/motivation –– during the tasks. This helped to ensure that the scanner would detect contrasts in brain circuit responses to high interest versus low interest peers.

Although the faces were selected by the researchers for their happy expressions, their attractiveness was random, so that they appeared to be a mix of typical peers encountered by teens.

As expected, the teen participants deemed the same faces they initially chose as high interest to be the peers most interested in interacting with them. Older participants tended to choose more faces of the opposite sex than younger ones. When they appraised anticipated interest from peers of high interest compared with low interest, older females showed more brain activity than younger females in circuitry that processes social emotion.

"This developmental shift suggested a change in socio-emotional calculus from avoidance to approach," noted Pine. The circuit is made up of the nucleus accumbens (reward and motivation), hypothalamus (hormonal activation), hippocampus (social memory) and insula (visceral/subjective feelings).

By contrast, males showed little change in the activity of most of these circuit areas with age, except for a decrease in activation of the insula. This may reflect a waning of interpersonal emotional ties over time in teenage males, as they shift their interest to groups, suggest Pine and colleagues.

"In females, absence of activation in areas associated with mood and anxiety disorders, such as the amygdala, suggests that emotional responses to peers may be driven more by a brain network related to approach than to one related to fear and withdrawal," said Pine. "This reflects resilience to psychosocial stress among healthy female adolescents during this vulnerable period."

 

Nodes of a brain circuit for social emotion and approach behavior activated more in teenage girls than in boys with age. Functional MRI data (red) superimposed on anatomical MRI images.

Source: NIMH Emotion and Development Branch

 

Teenage participants were first asked to rate their interest in peers with whom they might communicate in an internet chat room (left). Two weeks later, while in a brain scanner, they were asked to rate how interested the same peers were in interacting with them (right).

Source: NIMH Emotion and Development Branch

Reference

Probing the neural correlates of anticipated peer evaluation in adolescence. Guyer AE, McClure-Tone EB, Shiffrin ND, Pine DS, Nelson EE. July 2009, Child Development.

Two Great YouTube Videos on Adolescents and Anxiety

Great Informational Websites Created by Dr. Speller and Dr. Korkosz:

• Stress and the Human Brain
• Early Life Stress and the Immune System
• The Facts About Major Depressive Disorder
• The Parent's Guide to Understanding Adolescent Depression

Sources: National Institute of Mental Health, Also see blogposts in Adolescents and Young Adults

Additional Resources:

• For related articles on the Web, click on: “Sphere: Related Content” located at the bottom of this blog post.
• For related books or blog posts with related content in Dr. Jeff’s and Dr. Tanya’s Blog type in the keywords into “Google Search” located in the sidebar.
• For more books with related content, type in the keywords into “Amazon Search” on the Amazon banner located in the side bar.
• To get the definition of any term in the blog, double chick on the term

Dr. Jeffrey Speller

Dr. Tanya Korkosz

Psychopharmacology Associates of New England

www.psychopharmassociates.com