08 Mar 2004

In the current Archives of General Psychiatry, George Uhl and Robert Grow from the National Institutes of Health compile an overview of the known genetic components of major brain diseases and then apportion the cost to society accordingly. AD comes out as the second most costly brain disorder in the United States, after addiction to alcohol, other drugs, and tobacco. The authors remind us that many neuropsychiatric disorders, including Parkinson’s (PD), Alzheimer’s (AD), and even Huntington’s diseases (HD), result from the interplay among multiple genes that bestow heritability in a complex non-Mendelian pattern. Because of the high cost of complex genetics to society, the authors urge researchers to reevaluate their strategies for identifying gene variants that might contribute to vulnerabilities to brain disorders.

In most cases of neuropsychiatric disease, inheritance of disease vulnerabilities is governed by complex genetics that cannot be explained by a specific gene on a chromosomal region. Rather, multiple genes have variants or mutations that can cause disease and limit the range of therapies a physician can employ. In classical Mendelian inheritance, nearby alleles on the same chromosome are inherited together, hence the success of linkage studies in finding disease genes. However, these forms of a given disease rarely account for more than two percent of its total burden. For example, rare alleles of the APP, PS1, and PS2 genes are classical and account for about two percent of cases, while more common alleles of the ApoE gene are risk factors for AD that bump its overall heritability up to about 50 percent.

Turning to the economic burden imposed by these disorders, the authors estimate that complex genetics account for most of their cost. In an overview table, the authors list U.S. cost estimates of overall heritability, Mendelian inheritance, and complex genetics for the following disorders: addiction, AD, PD, HD, pain, trauma, anxiety disorders, schizophrenia, depressive illnesses, developmental disorders, stroke, multiple sclerosis, and seizures. For example, the total cost of AD is put at $170.86 billion annually; its genetic component at $90.56 billion. Of that, the cost of Mendelian cases is $3.42 billion, while the complex genetics sets the country back $87.45 billion a year.

Environmental factors influence susceptibility to these complex brain disorders at all levels, the authors argue. They affect the expression of risk inherited by complex genetics, but they also drive age-of onset in rare Mendelian diseases. The modification of disease phenotype by environmental factors affects even HD, which—genetically speaking—is considered to be one of the simpler neurodegenerative diseases because its inheritability is 100 percent, and all of that is thought to be Mendelian. In fact, Nancy Wexler from Columbia University and the U.S.-Venezuela Collaborative Research Project report in last week’s PNAS Early Edition that Venezuelan HD kindreds showed significant variability in symptoms and age of onset despite identical numbers of CAG repeats in their huntingtin gene. The researchers conclude that environmental modifiers such as sanitation, poverty, poor diet, and pollutants all influence age of onset, which was thought to be governed by number of CAG repeats. The authors calculated that 40 percent of the variance in age of onset among the kindreds was attributed to genes, while environmental factors contributed to the remaining 60 percent. Likewise in AD, different carriers in a given family with an APP, PS1, or PS2 mutation can vary by many years in their age of onset, but the nature of the modifying factors is not yet known.

Taken together, cost and heritability data suggest that genetic research should focus less on linkage studies and more on association methods to reveal links between genetic disease susceptibility and pathogenic phenotypes, Uhl and Grow write. With increasing information about human variation becoming available, the authors of both papers encourage researchers to delve deeper into investigating gene variants and integrating this information with environmental influences that may modify them.—Erene Mina