Dean A. HaycockSpecial To BioWorld Today

It took skill, money, time and some luck, but geneticists havesuccessfully tracked down stretches of DNA that, in too manyinstances, determine our fate. Scientists have identified genesassociated with Alzheimer's disease, Huntington's disease, cysticfibrosis, Duchenne's muscular dystrophy, breast cancer and coloncancer. Each discovery created newspaper headlines when it wasannounced. But today, to many scientists, these discoveries look likethey may have been the "easy" ones.

The "hard" ones are the relatively common diseases over whichgenes have a clear but perhaps more subtle influence: diabetes,depression, schizophrenia. In recent years, headlines have impliedthat genes for these common but complex diseases had beenpinpointed but the findings were not replicated in the scientificliterature.

Now, Neil Risch, of Stanford University in Palo Alto, Calif., andKathleen Merikangas, of Yale University School of Medicine in NewHaven, Conn., said they wonder if "the genetic study of complexdisorders has reached its limits?" In an article in the Sept. 13 issue ofScience, "The future of genetic studies of complex human disease,"Risch and Merikangas suggest that linkage analysis _ the methodused to successfully track down most disease genes so far _ is notgoing to be helpful in tracking down genes which exert modest orslight influences on disease expression.

Identification of genes affecting complex diseases such as depressionand schizophrenia, the authors said, could more readily be achievedby using a different gene-testing strategy called association studies."They have really shown the way to go is towards association studiesas opposed to linkage," said Bronya Keats, laboratory and statisticalgeneticist at the Louisiana State University Medical Center.

The Basic Differences

Linkage and association studies differ in their approach to matching adisease with a gene.

"Linkage studies are basically a `within family' design in which theassociation between genetic markers and disease is examined amongaffected and unaffected members of the family," Merikangasexplained. She added that a variation of the linkage analysis approachis the "affected sib pair method." This type of linkage studyinvestigates concordance for genetic markers only between a pair ofsiblings with the disease.

"In contrast, association studies do not use information fromfamilies," Merikangas said, "but rather collect samples of affectedindividuals and unaffected individuals. An association is inferredwhen there is an increased frequency of a particular genetic markeramong the affected individuals compared to the unaffectedindividuals."

Another type of association study is called "the haplotype relativerisk method."

"It uses the genes that are not transmitted from parents [each parenttransmits only one of a pair of genes] to an affected child as controlmarkers, rather than sampling a series of unaffected individuals fromthe general population. One then compares the frequency of aparticular genetic marker allele in affected persons with the frequencyof the non-transmitted allele in the parents," Merikangas explained.

Linkage studies require that geneticists assume a specific mode ofinheritance (e.g., dominant, recessive, etc.) in pedigrees. The affectedsib pair method, on the other hand, does not require assumptionsregarding a mode of transmission.

The authors use hypothetical statistical genetic models to show thatassociation studies will yield better results than linkage analysis in thefuture. That future depends on further technological developments.Association analysis requires that the disease gene or genes and theirvariations must tentatively be identified before testing can begin. Andvery large numbers of these variations, called polymorphisms, willhave to be identified and tested. With today's technology, that is toolarge a task to undertake. But Keats said the technological advancesthat will enable this massive search are coming.

"There is a lot going on to detect polymorphisms and identifyinggenes," she said. One spin-off benefit of the human genome project,Risch and Merikangas noted, could be the identification ofpolymorphisms for all human genes.

"There is no doubt the way to really find these genes is to have themin hand, all 100,000 genes or so, and then to go through them lookingfor the ones that have an effect on a particular phenotype," Keatssaid.

The promise of association studies raises an interesting question forKeats.

"How much should we continue with what we are doing now, whichis keeping a lot of labs in business knowing that really most of ouranswers are going to come when we have this breakthrough intechnology?" Keats said, adding she believes the main argument forcontinuing linkage studies is that everything being done now will beuseful for association studies in the future.

As the authors note, samples already collected for linkage studies andnow stored in freezers in labs around the world can be used for futureassociation studies after molecular technologists have developed thetechnology to identify, test and screen large numbers ofpolymorphisms.

"If industry can develop the technology for large-scale screening,this could have a large impact," Risch said.

In the meantime Risch and Merikangas are busy determining the mostefficient study designs to detect genes for complex disorders.

"We have continued our work in three areas: collecting informationregarding patterns of familial aggregation of these conditions toidentify the extent to which genetic factors are involved in theirexpression; developing more precise and valid definitions of thedisorders to reduce the heterogeneity in the samples; and further workon statistical methods to develop more powerful association tests,"Merikangas said.

The use of association studies promises to make the remaining "hard"problems in establishing the genetic basis of complex disorders a loteasier in the future. n

(c) 1997 American Health Consultants. All rights reserved.

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