ScienceWeek

THE BURDEN OF COMPLEX GENETICS IN BRAIN DISORDERS

The following points are made by G.R. Uhl and R.W. Grow (Arch Gen Psychiatry. 2004;61:223-229):

1) The magnitude of complex genetic influences has not been clearly delineated for disorders of the brain and nervous system. The authors define complex genetic influences as those that are genetic but not due to the single-gene effects that produce mendelian inheritance patterns. Defining the magnitude of these complex genetic influences is not easy: there is varying precision and/or agreement about the ways that these disorders should be defined for studies of their costs and prevalence, how the sizes of the burdens that these diseases place on individuals and societies should be calculated, how overall heritable influences should be ascertained, and how contributions of single-gene inheritance should be estimated. The authors use available data concerning each of these issues to estimate the magnitude of the US burden of brain and nervous system disorders attributable to complex genetics.

2) Some of the more common brain and nervous system problems can be listed in descending order of cost in the US as follows: addictions, Alzheimer disease and other dementias, pain and migraine, head and spinal cord injuries, anxiety disorders, schizophrenia, depressive illnesses, developmental disorders, stroke, Parkinson disease, multiple sclerosis (MS), seizures, and Huntington disease.(1-4) Taken together, these disorders should provide a good overall picture of the sum of neurological and psychiatric disorders due to these and other rarer illnesses. Disease definitions; estimates of the medical, judicial, lost productivity, and other societal costs; and the heritability estimates used herein come from various sources.(1-4) We can nevertheless identify evidence and/or estimate the extent of heritability and the degree to which single-gene or complex inheritance patterns contribute to the genetics for each of these disorders. The authors focus on cost as a primary measure. Fractional disease burdens that derive from many types of disorders can be most readily allocated using cost assessments.

3) Single-gene disorders ("mendelizing disorders") classically reveal themselves by the way in which they move through families (eg, 50% of offspring manifesting classic autosomal dominant disorders).(5) These disorders are readily analyzed with linkage approaches that typically use hundreds of DNA markers to rapidly identify the chromosomal regions that harbor genes in which allelic variants or mutations cause disease. The gene variants that cause single-gene disorders are usually found infrequently in US populations. However, each can make a large impact on the health of affected individuals. Such large influences of single-gene variants usually enable the variants to cause disease in many environments and on many genetic backgrounds, making it relatively easy to detect the causative gene variants. Unfortunately, these same features can also limit the range of new therapeutic options that arise when mendelizing gene variants are elucidated. Environmental changes that might effectively alter susceptibility to a more complex disorder are unlikely to provide much benefit in a classic highly penetrant mendelian disorder, such as Huntington disease.

4) Complex disorders can display substantial heritabilities, but they lack classic mendelian inheritance patterns.5-6 They are, thus, more frequent among family members of affected individuals than random individuals from the population. They are more frequent in the co-twins of genetically identical monozygotic twin probands than in the co-twins of dizygotic fraternal twins who share half of the proband's genes. Environmental factors and multigene inheritance based on allelic variants in several or many genes each contribute to the vulnerabilities to most of these disorders. Genetic heterogeneity and gene x gene and gene x environment interactions can each complicate analyses. The optimal methods for identifying the specific allelic variants that increase vulnerabilities to complex disorders are less well established than linkage methods in mendelizing disorders. However, several strategies are being used with success, including the sib pair and association methods.

5) The authors conclude: Brain and nervous system disorders may cost the US as much as $1.2 trillion annually, and affect many millions of Americans each year. Twin data suggest that more than 40% of the societal burden of brain disorders is likely to be genetically mediated. Most of this disease burden arises from complex multigene genetics as well as from environmental influences. The authors suggest the large sizes of these complex genetic burdens should encourage careful molecular and clinical work to link disease-vulnerability allelic variants with the pathogenesis, nosologic characteristics, prevention, diagnostics, and therapeutics of brain disorders.

References (abridged):

1. Lewin. Decade of the Brain: Burden of Brain Disorders. Falls Church, Va: National Foundation for Brain Research; 1992

2. Rice DP. Economic burden of mental disorders in the United States. Econ Neurosci. 1999;1:40-44

3. Rice DP. Economic costs of substance abuse, 1995. Proc Assoc Am Physicians. 1999;111:119-125

4. Murray CJL, Lopez AD, eds. The Global Burden of Disease. Geneva, Switzerland: World Health Organization; 1996

5. Ott J. Analysis of Human Genetic Linkage. Baltimore, Md: Johns Hopkins University Press; 1999

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