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Thinking Outside The Block In Disease Gene Studies

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Thinking Outside The Block In Disease Gene Studies

http://www.medicalnewstoday.com/articles/177071.php

In the decade since the Human Genome Project produced the first map of DNA

sequences in the human genome, scientists throughout the world have combed

through genome data to identify genes and gene variants that cause human

disease. A new study suggests that researchers may need to broaden their search

farther afield to pinpoint rare but powerful disease-causing mutations.

Researchers from two large genome research centers at The Children's Hospital of

Philadelphia and at Duke University published a study today in the online

journal Public Library of Science Biology (PLoS Biology), describing what they

call " synthetic genome-wide associations. "

" We believe our analysis will encourage genetics researchers to reinterpret

findings from genome-wide association studies, which will also enable all of us

to generate more meaningful diagnostic results for patients, " said co-author

Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at

The Children's Hospital of Philadelphia.

Hakonarson and his colleague at Children's Hospital, Kai Wang, Ph.D.,

collaborated closely with the study leader, B. Goldstein, Ph.D., of the

Center for Human Genome Variation at Duke University. Both research teams had

been working independently and simultaneously on a hypothesis that rare genetic

variants had a larger role in disease than conventionally assumed.

When Goldstein presented his conceptual model last year to genetics researchers

at the University of Pennsylvania, Hakonarson and Wang proposed a collaboration,

subsequently supplying data from two genetic diseases-sickle cell disease and

genetic hearing loss-that supported and validated the rare variant hypothesis

proposed in the current paper.

To date, genome-wide association studies (GWAS) have detected many common gene

variants associated with particular diseases, but those variants have shown only

modest effects, accounting for a very small percentage of the genetic

contribution to the disease.

" GWAS is a very powerful tool to identify disease genes, but for complex

disorders, these common variants may not reflect true effect sizes, " said

Hakonarson. " We may need to look farther away from those common variants to find

variants that are individually rare but have strong causative effects. " The

genetic variants being tested, also referred to as single-nucleotide

polymorphisms (SNPs), are changes in a single chemical base of DNA that act as

markers for a disease, without causing the disease.

In the current study, the researchers performed a computer simulation in which

rare variants were distributed throughout 10,000 genotypes (models of DNA data

simulating those collected from human study subjects). Their analysis yielded

" synthetic associations " - statistical connections between the rare variants and

the common variants that produced signals similar to those found in actual

disease studies.

They then tested their approach on two large sample sets for well-characterized

disorders, sickle cell disease and genetic hearing loss, in which causative

genes were already known. They found a similar pattern of synthetic associations

between rare and common gene variants. " Under conventional interpretations, GWAS

found only modest contributions for associations with the gene that we know

causes hearing loss, " said Hakonarson. " Our study shows that conventional

interpretation may undervalue the contribution of such gene variants in hearing

loss, and we suggest that similar underrepresentation of effect sizes by common

variants may occur in many other genetic disorders. "

The usual assumption in GWAS is that disease-causing variants are located

relatively close to the common variants that capture them (referred to as

tagging SNPs). Researchers usually seek out causative variants that travel

together with the common variant along the genome; in technical terms, the

nucleotides are in relatively strong linkage disequilibrium. " Our study found

the causative genes may be two to four times farther away than researchers tend

to search, so their effect sizes are poorly captured, " said Hakonarson.

Hakonarson and Wang are conducting follow-up studies, some in collaboration with

Goldstein, to expand and refine the gene-hunting model using resequencing

techniques. The immediate implications of this model, said Hakonarson, affect

researchers more than clinicians. But eventually, he adds, this work may improve

diagnostic evaluation for patients, furthering the goal of personalized medicine

tailored to a patient's genetic profile. At the same time, technological

advances in automated gene sequencing will enable researchers to work faster as

well as smarter.

The Children's Hospital of Philadelphia and the Institute for Genome Sciences

and Policy at Duke University provided funding support for this study.

Co-authors with Goldstein, Hakonarson and Wang were P. Dickson, of the

Center for Human Genome Variation at Duke University; and Ian Krantz, M.D., of

the Division of Human Genetics at Children's Hospital, an expert in genetic

hearing loss.

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