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Home » News » Schizophrenia News » How Genes Influence Mental Health How Genes Influence Mental HealthResearchers are gaining insight as to how genes work to impair various aspects of attention, memory and perception — the behaviors associated with many psychiatric illnesses, such as schizophrenia, bipolar disorder and depression. New studies shed new light on how specific genes contribute to the susceptibility to and pathology of schizophrenia, bipolar disorder and depression, some of the most severe, chronic and disabling mental illnesses that collectively affect an estimated 40 million Americans. Coming at a time when some treatments for mental illnesses are a matter of trial and error, these findings have relevance in the development of novel therapies targeted to specific patients and to specific genes. Donald C. Goff, M.D., director of the Schizophrenia Clinical and Research Program at Massachusetts General Hospital and a leading researcher on the role of genetics in the development of new treatments for schizophrenia, moderated the discussion. Folate as a Cause and Treatment for Schizophrenia: Who Will Benefit? Do genes explain why some people with schizophrenia are helped when they take supplements of the common B vitamin, folate? The answer is yes and now, new NARSAD funded research is examining the reasons why. According to Dr. Goff, whose pioneering research identified a link between low blood levels of folate and negative schizophrenia symptoms, folate is involved in many different chemical pathways in the brain, including keeping levels of the amino acid homocysteine low. When homocysteine levels are too high, this interferes with the functioning of receptors located all over the brain — called NMDA ( N-methyl-D-aspartate) receptors — that are critical to learning, memory, brain development, and general neural processing. However, what causes low folate in people with schizophrenia is still open to question. One reason, confirmed by epidemiological studies, is poor dietary intake. Based on examining two major famines in the 20th century — the Dutch Hunger Winter of 1944-45 brought about by the Nazi occupation in World War II and the Chinese famine in 1959-61 — scientists found that the incidence of schizophrenia among children born to women who were pregnant during these famines increased two-fold. But in most cases, starvation is not the problem. That is why Dr. Goff’s team looked for other causes, including two genes: GCPII (glutamate carboxypeptidase II), which controls the absorption of folate and may be deficient in people with schizophrenia, and MTHFR (methylenetetrahydrofolate reductase), which activates folate for use in the brain. Using this information, Dr. Goff and his colleagues are recruiting patients for a large trial to determine whether folate supplementation will help individuals affected by these genes, many of whom have treatment-resistant psychotic symptoms. Funded by the National Institute of Mental Health, this double-blind study will follow 150 patients with schizophrenia at three sites over a 16-week period. “Schizophrenia is a prevalent and costly disorder and can be very difficult to treat. This is especially true for the estimated 30 percent of patients with treatment-resistant psychotic symptoms, who may also experience social withdrawal, apathy, and depression,” Dr. Goff said. “Having these new data will validate whether folate, which is known to be very safe, is an effective way to improve outcomes for people with schizophrenia who now suffer from treatment-resistant psychotic symptoms.”

Building on this landmark research, scientist and colleague, Joshua Roffman, M.D., is using NARSAD funds to go the next step — identifying people with schizophrenia who are most likely to benefit from folate supplementation. Here, Dr. Roffman and his colleagues started with the MTHFR gene and found that one variant increases the severity of schizophrenia symptoms. Moreover, in patients with this variant, low folate intake was associated with symptoms that were especially severe. Now, Dr. Roffman’s team is looking at the combination of MTHFR and another gene — COMT (catechol-Omethyltransferase) — that affects dopamine levels in the brain. Although the two genes have separately been associated with schizophrenia, Dr. Roffman’s just completed study finds that when these genes interact, a specific subset of patients is at greater risk for cognitive impairment. In individuals who carry the risk variants of both MTHFR and COMT, lower-than-normal levels of dopamine in the part of the brain called the prefrontal cortex may cause problems with information processing and working memory. Using functional neuroimaging, Dr. Roffman and his colleagues also found that the same combination of MTHFR and COMT variants were associated with abnormally low activity in the prefrontal cortex. Genes and Depression If a better understanding of genes may lead to customized therapies for schizophrenia, can the same be true for new depression treatments? Answering this question is especially important now that a 2006 government study found that a significant number of people with clinical depression – more than half – are not helped by their initial course of antidepressant treatment, whether medication or talk therapy. In addition, antidepressant medications often come with troubling side effects, such as sleep changes, sexual problems, headaches and gastrointestinal problems, and an analysis by the Food and Drug Administration has shown that antidepressants may cause suicidal thinking and behavior in children, adolescents and adults ages 18 to 24. According to Roy Perlis, M.D., M.Sc., the director of pharmacogenomics research at Massachusetts General Hospital’s Department of Psychiatry, specific genes may influence how individual patients respond to antidepressant therapies, which is why his research team is using NARSAD funds to try to find these genes. After studies in mice identified variations of four genes that may affect how individuals respond to antidepressant treatment, Dr. Perlis and his colleagues examined these four genes in DNA samples provided by 1,554 people participating in a large government study called the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. What the team found was a link between a variation in the gene TREK1 and poorer response to antidepressant treatment. Family Traits Provide Clues to Genes for Schizophrenia, Bipolar Disorder It is also important to identify the endophenotypes — traits associated with a clinical disorder — that can serve as a roadmap for detecting disease-related genes. That is why Deborah L. Levy, Ph.D., associate professor of psychology in the Department of Psychiatry at Harvard Medical School and director of the Psychology Research Laboratory at McLean Hospital, is studying families to detect relatives who are carriers of the genes for schizophrenia and bipolar disorder, even though these individuals don’t have the diseases themselves. “One of the key issues in any genetic study is to distinguish individuals who are gene carriers from individuals who are not gene carriers,” explained Dr. Levy. In single gene disorders, such as cystic fibrosis and Huntington’s disease, 25 percent and 50 percent of family members, respectively, have the same illness. In contrast, only 6.5 percent of family members of people with schizophrenia actually have the illness, which means most relatives don’t have symptoms of the illness but may still be gene carriers. To find the relatives who are likely carriers of genes for schizophrenia and bipolar disorder, Dr. Levy and her colleagues have zeroed in on four discernable schizophrenia-related traits that occur in well family members at a

much higher rate than schizophrenia itself: difficulty following a slow moving target with one’s eyes, syntax errors or idiosyncratic use of language, subtle anomalies involving the midline of the face , and difficulty filtering out noises and other irrelevant stimuli (a condition known as sensory gating). These traits, according to Dr. Levy, are much more common in families with schizophrenia. For example, idiosyncratic use of language (a trait similar to the thought disorder observed in schizophrenia) occurs in 37 percent of clinically unaffected first-degree relatives of individuals with schizophrenia, a rate that is almost six times higher than schizophrenia in the same families. When the rates for thought disorder and schizophrenia and related clinical conditions are combined, the proportion of potential gene-carrying relatives is close to 50 percent, consistent with a dominant gene, and much higher than the 6.5 percent rate of schizophrenia in the same families

Home » News » Relationships and Sexuality News » Genes Influence Relationship Satisfaction Genes Influence Relationship Satisfaction By Rick Nauert PhD Senior News Editor Reviewed by John M. Grohol, Psy.D. on January 30, 2007 The unraveling of the human genome has spanned a new appreciation for our myriad hardwired genetic influences. Provocative new research expands the genetic predilections to include a new domain –- the selection of a partner for a relationship and the obtainment of sexual satisfaction. A study published in Psychological Science has found a link between a set of genes involved with immune function and partner selection in humans. In fact, the new research suggests that choosing a mate may be partially determined by your genes. According to the authors, vertebrate species and humans are inclined to prefer mates who have dissimilar MHC (major histocompatibility complex) genotypes, rather than similar ones. This preference may help avoid inbreeding between partners, as well as strengthen the immune systems of their offspring through exposure to a wider variety of pathogens. The study investigated whether MHC similarity among romantically involved couples predicted aspects of their sexual relationship. “As the proportion of the couple’s shared genotypes increased, womens’ sexual responsivity to their partners decreased, their number of extra-pair sexual partners increased and their attraction to men other than their primary partners increased, particularly during the fertile phase of their cycles,” says Christine Garver-Apgar, author of the study. This study offers some understanding of the basis for romantic chemistry, and is the first to show that compatible genes can influence the sexual relationships of romantic couples. Source: Blackwell Publishing Home » News » Mental Health and Wellness News » Complex Genetic Influence for Alzheimer’sComplex Genetic Influence for Alzheimer’s By Rick Nauert PhD Senior News Editor Reviewed by John M. Grohol, Psy.D. on January 18, 2008 Mayo Clinic researchers have found strong evidence that genes other than the well-known susceptibility risk factor APOE4 influence the risk for developing the neurodegenerative disease.

Researchers at Mayo Clinic Jacksonville studied 25 multigenerational families of individuals diagnosed with late onset Alzheimer’s disease (LOAD), the most common form of the disorder. The scientists found that blood levels of amyloid beta (Aß) proteins associated with AD were significantly elevated compared to protein found in non-blood relatives, such as spouses. These first-degree relatives were cognitively normal and age 65 or less — many of them too young for symptoms of LOAD to show up. “These results indicate that genetic factors of substantial magnitude lead to significant elevations of Aß in the blood of asymptomatic, young individuals from extended LOAD families,” says the study’s lead investigator, Nilufer Ertekin-Taner, M.D., Ph.D. “This fits with our hypothesis that Aß levels rise years before development of the disorder.” The results, which first appeared online in October of last year, will be published in the Feb. 19 issue of Neurology. The researchers have already identified three candidate genes on chromosome 10 that is associated with LOAD, and at least one of them, the gene that produces insulin degrading enzyme (IDE), is now regarded as a prime candidate for contributing to the disease. IDE degrades both insulin and amyloid protein, and scientists hypothesize that when there is too much insulin in the brain such as due to diabetes or lower expression levels of IDE, this may lead to toxic accumulation of Aß. “We believe that 60 percent of the risk of developing the most common form of Alzheimer’s disease is genetic, and a good part of that is APOE4. But other genes are certainly contributing, and they could provide a platform for diagnosis and therapy in the future,” says the study’s senior author, Neill Graff-Radford, M.B.B.Ch., FRCP. Dr. Ertekin-Taner estimates that the impact of these three genes could be as large as APOE4, which is a variant of the APOE gene that has been linked to LOAD. “Between 30 percent and 70 percent of AD can be attributable to APOE, and we estimate this locus of three genes on chromosome 10 could be as important,” she says. “The effect of the chromosome 10 locus could be due to multiple genes, with each gene having a smaller effect size than that of APOE.” This study represents a decade of work by the Mayo researchers, who have been instrumental in discovering that one form of Aß known as Aß42 is much more toxic than the other common form of Aß, which is Aß40. They have also demonstrated that as AD progresses, Aß42 levels that have been rising for years begin to decline, presumably because more and more of the protein is being deposited within the brain. Source: Mayo Clinic

Home » News » Psychotherapy News » Genes Influence Susceptibility to Alcohol Genes Influence Susceptibility to Alcohol By Rick Nauert PhD Senior News Editor Reviewed by John M. Grohol, Psy.D. on November 7, 2008 A new study suggests genetic factors control variations in a certain region of the brain, which could in turn be partly responsible for increased susceptibility to alcohol dependence. It appears that the size of the right orbito frontal cortex (OFC), an area of the brain that is involved in regulating emotional processing and impulsive behavior, is smaller in teenagers and young adults who have several relatives that are alcohol dependent.

In the research, which was published this week in the early online version of Biological Psychiatry, Dr. Shirley Hill, Ph.D., professor of psychiatry, University of Pittsburgh School of Medicine and her team imaged the brains of 107 teens and young adults using magnetic resonance imaging. They also examined variation in certain genes of the participants and administered a well-validated questionnaire to measure the youngsters’ tendency to be impulsive. The participants included 63 individuals who were selected for the study because they had multiple alcoholdependent family members, suggesting a genetic predisposition, and 44 who had no close relatives dependent on drugs or alcohol. Those with several alcohol-dependent relatives were more likely to have reduced volume of the OFC. When the investigators looked at two genes, 5-HTT and BDNF, they found certain variants that led to a reduction in white matter volume in the OFC, and that in turn was associated with greater impulsivity.“We are beginning to understand how genetic factors can lead to structural brain changes that may make people more vulnerable to alcoholism,” Dr. Hill said. “These results also support our earlier findings of reduced volume of other brain regions in high-risk kids.” These differences can be observed even before the high-risk offspring start drinking excessively, she added, “leading us to conclude that they are predisposing factors in the cause of this disease, rather than a consequence of it.”Source: University of Pittsburgh Schools of the Health Sciences Home » News » Schizophrenia News » Cellular Origins of Schizophrenia Cellular Origins of Schizophrenia By Rick Nauert PhD Senior News Editor Reviewed by John M. Grohol, Psy.D. on May 13, 2008 Researchers have discovered how abnormalities in microRNAs, a family of molecules that regulate expression of numerous genes, may contribute to the behavioral and neuronal deficits associated with schizophrenia. The findings are illuminated in the journal Nature Genetics as Columbia University professors Maria Karayiorgou, M.D., and Joseph A. Gogos, M.D., Ph.D., explain how they uncovered a previously unknown alteration in the production of microRNAs. The alterations appear to influence a chromosome known to be associated with schizophrenia. “By digging further into this chromosome, we have been able to see at the gene expression level that abnormalities in microRNAs can be linked to the behavioral and cognitive deficits associated with the disease”, says Karayiorgou. The investigators modeled mice to have the same genetic deletion as the one observed in some individuals with schizophrenia and examined what happens in the expression of over 30,000 genes in specific areas of the brain. The significance of this work is that it implicates a completely novel, previously unsuspected group of susceptibility genes and brings investigators a step closer to understanding the biological mechanisms of this disorder. Implication of such a large family of genes (the most recent estimate puts the number of human microRNAs at at least 400 that influence the expression of as many as a third of all genes) could partly account for the genetic complexity associated with this devastating disorder and explain some of the difficulties that the researchers have encountered in their efforts to pinpoint individual genes. Source: Columbia University Genes, Environment, or Both?A number of studies show that race differences are caused by both genes and environment. Heritabilities, cross-race adoptions, genetic weights, and regression to the average all tell the same story. Cross-race adoptions give some of the best proof that the genes cause rare

differences in IQ. Growing up in a middle-class White home does not lower the average IQ for Orientals nor raise it for Blacks. Can any environmental factor explain all the data on speed of dental development, age of sexual maturity, brain size, IQ, testosterone level, and the number of multiple births? Genes seem to be involved. But how can we know for sure? Some traits are clearly inherited. For example, we know that the race differences in twinning rate are due to heredity and not to the environment. Studies of Oriental. White, and Mixed-Race children in Hawaii and of White. Black, and Mixed-Race children in Brazil show that it is the mother's race, and not the father's, that is the determining factor. But the role of racial heredity is found for other traits as well. Heritability Studies Heritability is the amount of variation in a trait due to the genes. A heritability of 1.00 means that the differences are inborn and the environment has no effect. A heritability of zero (0.00) means the trait is controlled by the environment and not at all by the genes. A heritability of 0.50 means that the differences come from both the genes and the environment. Heritability is useful for animal breeders. They like to know how much genes influence things like milk yields and beefiness in cattle or determine which dogs can hunt, and which are good with children. The higher the heritability, the more the offspring will resemble their parents. On the other hand, low heritabilities mean that environmental factors like diet and health are more important. For people, we measure heritability by comparing family members, especially identical with fraternal twins, and adopted children with ordinary brothers and sisters. Identical twins share 100% of their genes, while fraternal twins share only 50%. Ordinary brothers and sisters also share 50% of their genes, while adopted children share no genes. If genes are important, identical twins should be twice as similar to each other as are fraternal twins or ordinary siblings – and so they are. Some identical twins are separated early in life and grow up apart. The famous Minnesota Twin Study by Thomas J. Bouchard and others compared many of these. (See Chart 8). Even though they grew up in different homes, identical twins grow to be very similar to each other. They are similar both in physical traits (like height and fingerprints) and in behavioral traits (like IQ and personality). Identical twins who grow up in different homes share all their genes but do not share the effects of upbringing. As you can see in Chart 8, heredity accounted for 97% of the difference for fingerprints, and the environment only 3% Social attitudes were 40% heredity, 60% environment. IQ was 70% heredity, 30% environment. Identical twins are often so alike that even close friends cannot tell them apart. Although the twins in the Minnesota Project lived separate lives, they shared many likes and dislikes. They often had the same hobbies and enjoyed the same music, food, and clothes. Their manners and gestures were often the same. The twins were very alike in when they got married (and sometimes divorced) and in the jobs they held. They even gave similar names to their children and pets. One of these pairs, the "Jim twins," were adopted as infants by two different working- class families. But they marked their lives with a trail of similar names. Both named their childhood pet "Toy". Both married and divorced women named Linda and then married women named Betty. One twin named his son James Allen, the other named his son James Alan.

Another pair of separated twins were helpless gigglers. Each twin said her adoptive parents were reserved and serious. Each one said she never met anyone who laughed as easily as she did – until she met her twin! Heredity also affects the sex drive. The age of our first sexual experience, how often we have sex, and our total number of sexual partners all have heritabilities of about 50%. So do the odds that we will get divorced. Several studies find that homosexuality, lesbianism, and other sexual orientations are about 50% genetic. Twin studies show that even social attitudes are partly genetic in origin. One Australian study of 4,000 twin pairs found there was a genetic influence on specific political beliefs like capital punishment, abortion, and immigration. It turns out that criminal tendency is also heritable. About 50% of identical twins with criminal records have twins with criminal records, while only about 25% of fraternal twins do. Genes influence helping behavior and aggression. A large study of British twins found that the desire to help or hurt others has a heritability of around 50%. For men, fighting, carrying a weapon, and struggling with a police officer are all about 50% heritable. My article in the 1989 Behavioral and Brain Sciences shows that who we marry and who we choose as friends is also partly genetic. When the blood groups and heritabilities of friends and spouses are compared, we find that people chose partners who are genetically similar to themselves. The tendency for like to attract like is rooted in the genes. Adoption Studies A good check on the results of twin studies comes from adoption studies. A Danish study (in the 1984 issue of Science) examined 14,427 children separated from their birth parents as infants Boys were more likely to have a criminal record if their birth parents had a criminal record than if their adoptive parents did. Even though they were brought up in different homes, 20% of the full brothers and 13% of the halfbrothers had similar criminal records. Only 9% of the unrelated boys brought up in the same home both had criminal records. The Colorado Adoption Project found that genes increase in influence as we age. Between age 3 and 16, adopted children grew to be more like their birth parents in height, weight, and IQ. By age 16 the adopted children did not resemble the people who had reared them. The heritability of height, weight, and IQ in infancy are all about 30%. By the teenage years, they are about 50% and by adulthood, they are about 80%. Thus, as children grow older, their home environments have less impact and their genes have more impact, just the opposite of what culture theory predicts.