|T H E N I H C A T A L Y S T||N O V E M B E R D E C E M B E R 2004|
by Fran Pollner
Brain explorers: (left to right) David Goldman, NIAAA; Robert Nussbaum, NHGRI; Daniel Weinberger, NIMH; and George Uhl, NIDA
The contribution of multiple genes to the expression of a given disorder may be harder to pin down than Mendelian genetics, but the more complex the underlying genetics, the more numerous the potential pathways to intervention.
Unlike "deterministic" single-gene causes of such conditions as cystic fibrosis or Huntingtons disease, susceptibility genes merely predict an increased risk of associated disordersan increased risk that once identified may be preempted, panelists said at a Research Festival symposium.
In the realm of common brain disorders, plowing through the genomic jungle to track alleles of vulnerability may help alter the course of some of the most pervasive, complicated, and recalcitrant conditionsdrug abuse, alcoholism, and mental illness.
Addiction Vulnerability http://www.niaaa.nih.gov/intramural/web_lng/LN_Main/LNG.htm
Polydrug abusers seen at NIDAs Baltimore campus are the basis for "bedside-to-bench research" that is identifying the allelic variants that predispose to addiction vulnerability.
George Uhl, chief of the NIDA Molecular Neurobiology Branch, described studies surveying thousands of single nucleotide polymorphisms (SNPs) that track how "DNA markers and addiction move together through a population."
Several markers, Uhl said, have been found to be close to the functional variants; similar associations were found among unrelated polysubstance abusers, with minimal differences from European American and African American cohorts.
"Although environment also provides a large chunk" in the development of addiction, Uhl said, "the results of gene mapping suggest that we have markers with predictive power in European, African American, and Asian populationsand current data nominate 33 chromosomal sites that together may explain a significant amount of addiction vulnerability."
Among those genes implicated in addiction vulnerability are NrCAM (neuronal cell adhesion molecule), a morphine-regulated gene, and the cannabinoid receptor gene CNR1.
As with other addictions, heritability accounts for more than 50 percent of vulnerability to alcoholism, said David Goldman, acting chief of the Laboratory of Neurogenetics, NIAAA.
This substantial impact of genetics, Goldman said, influences susceptibility to nicotine, marijuana, and heroin addictions.
Genes implicated in susceptibility to alcoholism include the ethanol metabolism genes ALDH2 (aldehyde dehydrogenase) and ADH1B (alcohol dehydrogenase) and COMT (catechol-O-methyl-transferase).
Although parkinsonism is rarely inherited, understanding the nature of the genetic pathway to the disease sheds light on how to arrive there sporadically, observed Robert Nussbaum, chief of the Genetic Disease Research Branch, NHGRI.
The clear finding that specific toxins that interfere with mitochondrial function cause Parkinsons disease (PD) and the equally obvious fact that most PD patients have no family history of the disease help explain why the genetics of PD has been explored only in the last eight years, he said.
What has surfaced thus farin twin studiesis that genetics comes into play in the context of early onset (before age 50) PD, with siblings the relatives at greatest risk.
Investigators at five other institutesNINDS, NIMH, NIA, NHLBI, and NIAAAare involved in research on PD genetics, Nussbaum said, noting that at least four PD loci have been identified, including a-synuclein (park 1, at 4q21) found in families in Greece, Italy, and Germany, and parkin, a ubiquitin E3 ligase (park 2, at 6q2527).
"A key lesson," in the pursuit of PD heritability, Nussbaum observed, "is that hard as it is to find genetic causes, 30,000 genes [are] easy compared [with] the black box of environmental factors."
The underlying hypothesis of research undertaken by Nussbaums team was that studying the rare Mendelian familiesthose with "deterministic" PD geneticswould elucidate the pathways to PD in the sporadic majority.
"We studied an early onset, autosomal dominant Italian family with linkage to 4q21 and found mutations." Another early-onset kindred, from Iowa, had no a-synuclein mutation, but, rather, three copies of a segment of chromosome 4a triplication of the gene, he said.
The team has identified allelic variants with negative and positive associations; related animal work has shown that overexpression of a-synuclein in Drosophila and mice results in a neurodegen-erative phenotype.
Nussbaum described collaborative studies with Eric Murphy of the University of North Dakota, Grand Forks, and Drake Mitchells lab in NIAAA examining brain phospholipid measures in the a-synuclein knockout mouse.
They focused on cardiolipin, a lipid specific to mitochondrial membrane that is required for electron transport. Abnormalities in cardiolipin may produce reactive oxygen species, disrupting the mitochondria.
The knockout model, he noted, was not sufficient to eliminate cardiolipin altogether. However, cardiolipin sidechains can be manipulated by dietary fatty acid.
Dietary studies with variable polyunsaturated fat constituents will look at whether "loss of function and aggregation of a-synuclein, with damaged or lost mitochondria, contribute to PD," Nussbaum said.
Cardiolipin effects have been studied mostly in yeast, he added, "but its an area ripe for study in mammals."
There is now clear proof, said Daniel Weinberger, chief of the Clinical Brain Disorders Branch, NIMH, that genes are strongly related to neural information processing systems, which in turn are related to behaviors and behavioral disorders. Thus, there is no longer any argument over the existence of a genetics of mental illness.
There are, however, questions regarding this genetics: "How many genes are involved, and how large is the effect of any one? What does it mean to be susceptible?" Weinberger asked. "We know about cancer genes and their effects on disruption of the cell cycle; biological susceptibility to mental illness and addiction is much more elusive."
The surprising finding, he said, is that linkage data have been at all successful in uncovering regions of the genome where susceptibility genes have been found. That success, he said, can be attributed at least partly to a "quirk of nature"the fact that linkage regions tend to harbor multiple susceptibility genes. This neighborly arrangement has facilitated replication, for instance, of the identification of schizophrenia genes among populations around the world.
Strategies that have been used to identify candidate genes in mental illness include expression profiling, SNP associations, and chromosomal translocation, Weinberger said. At NIMH, SNP association has identified evidence of at least 10 schizophrenia genes. He pointed to the identification of COMT and, more recently, GRM3 (glutamate receptor, metabotropic) as candidate genes in schizophrenia that have been studied extensively.
The COMT effect on dopamineit inactivates dopamine in the prefrontal cortexmay explain the apparent association of COMT variations with an array of phenotypic expressionspsychosis, obsessive-compulsive disorder, anxiety, drug abuse, bipolar disorder, aggression, poor impulse control, and sensitivity to pain. "It may seem preposterous," Weinberger said, "but this could be a basic biological effect" that manifests itself in a variety of ways in different contexts.
Cognition studies using functional MRI in his lab have shown that COMT contributes to normal human variation in prefrontal memory processing, which varies with COMT genotype.
Genes involved in serotonin signaling and reuptake, such as the serotonin transporter protein gene and its promoter, also predict for depression in the context of environmental stress. Not surprisingly, effecting change in serotonin signaling is the basis for most of the antidepressant drugs on the market today, Weinberger observed. n
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