Identification of the Genetic Basis for Complex Disorders by Use of Pooling-Based Genomewide Single-Nucleotide–Polymorphism Association Studies

Pearson, John V.; Huentelman, Matthew J.; Halperin, Rebecca F.; Tembe, Waibhav; Melquist, Stacey; Homer, Nils; Brun, Marcel; Szelinger, Szabolcs; Coon, Keith D.; Zismann, Victoria; Webster, Jennifer; Beach, Thomas G.; Sando, Sigrid Botne; Aasly, Jan; Heun, Reinhard; Jessen, Frank; Kölsch, Heike; Tsolaki, Magda; Daniilidou, Makrina; Reiman, Eric M.; Papassotiropoulos, Andreas; Hutton, Michael; Stephan, Dietrich A.; Craig, David W.

doi:10.1086/510686

Cited by 140 publications

(166 citation statements)

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“…A complete discussion of this new analytic approach is beyond the scope of the current manuscript, but numerous reviews are available for the interested reader. [91][92] The International Bladder Cancer Consortium is considering a GWAS, which has the potential to clarify the etiologic role of the candidate genetic pathways reviewed here, as well as characterizing gene/environment interactions that contribute to TCCUT carcinogenesis. Table 2 Family #2 CYP26 and NAT2 Polymorphism Phenotypes …”

Section: Discussionmentioning

confidence: 99%

Familial and genetic risk of transitional cell carcinoma of the urinary tract

Mueller¹,

Caporaso²,

Greene³

2008

Urologic Oncology: Seminars and Original Investigations

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Environmental exposures, including tobacco smoke and occupational exposure to aromatic amines, have been implicated in bladder cancer etiology. However, the pathogenesis of urinary bladder transitional cell carcinoma remains incompletely defined. In epidemiologic studies, family history confers a two-fold increase in bladder cancer risk, but it is uncertain whether this represents evidence of a genetic and/or a shared environmental basis for familial aggregation. Polymorphisms in genes involved in the metabolism of environmental toxins (e.g., NAT2) clearly modify individual susceptibility to bladder cancer. A genetic predisposition has also been suggested by case reports describing multiple-case families, and the development of bladder cancer in association with several well-described Mendelian disorders (e.g., HNPCC, retinoblastoma). Here we update a previouslyreported family, report a new multiple-case kindred, critically review previously-reported bladder cancer families and the epidemiologic literature related to family history of transitional cell carcinoma of the urinary tract (TCCUT) as a risk factor, as well as provide a brief summary of genetic factors that have been implicated in TCCUT risk. We conclude that familial TCCUT is either very uncommon or significantly under-reported, perhaps on the assumption that this is an environmental rather than a genetic disorder. The interaction between multiple genetic and environmental factors has made it challenging to identify genetic components responsible for many common diseases; therefore, a proposed genome-wide association study (GWAS) for urinary bladder cancer may help to clarify the etiologic role of the candidate genetic pathways reviewed here, as well as characterize gene/environment interactions that contribute to TCCUT carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Familial and genetic risk of transitional cell carcinoma of the urinary tract

Mueller¹,

Caporaso²,

Greene³

2008

Urologic Oncology: Seminars and Original Investigations

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“…Association identifies smaller chromosomal regions than linkage-based approaches. GWA fosters pooling strategies that preserve confidentiality and reduce costs, such as the microaray-based approaches that we and others have developed and extensively validated [68][69][70][71][72][73][74][75][76][77][78]. GWA provides ample genomic controls that can minimize the chances of unintended ethnic mismatches between disease and control samples.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“Higher order” addiction molecular genetics: Convergent data from genome-wide association in humans and mice

Uhl

Drgon

Johnson

et al. 2008

Biochemical Pharmacology

125

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Family, adoption and twin data each support substantial heritability for addictions. Most of this heritable influence is not substance-specific. The overlapping genetic vulnerability for developing dependence on a variety of addictive substances suggests large roles for "higher order" pharamacogenomics in addiction molecular genetics. We and others have now completed genomewide association (GWA) studies of DNAs from individuals with dependence on a variety of addictive substances vs appropriate controls. Recently reported replicated GWA observations identify a number of genes based on comparisons between controls and European-American and African-American polysubstance abusers. Here we review the convergence between these results and data that compares control samples and a) alcohol dependent European Americans, b) methamphetamine dependent Asians and c) nicotine dependent samples from European backgrounds. We also compare these human data to quantitative trait locus (QTL) results from studies of addiction-related phenotypes in mice that focus on alcohol, methamphetamine and barbiturates. These comparisons support a genetic architecture built from largely-polygenic contributions of common allelic variants to dependence on a variety of legal and illegal substances. Many of the gene variants identified in this way are likely to alter specification and maintenance of neuronal connections. KeywordsAssociation genome scanning; substance dependence; microarray; pooled; neuronal connections * To whom correspondence should be addressed at: Molecular Neurobiology, Box 5180, Baltimore, MD 21224 phone: (410) 550-2843 x 146, fax: (410) 550-1535, guhl@intra.nida.nih.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access A. Studies of human addiction vulnerabilitiesVulnerability to addictions is a complex trait with strong genetic influences that are largely shared by abusers of different legal and illegal addictive substances [1][2][3][4]. This conclusion comes from family, adoption and twin studies. Family studies clearly document that first degree relative (eg sibs) of addicts display greater risk for developing substance dependence than more distant relatives [1,5]. Adoption studies consistently find greater similarities between substance abuse phenotypes with biological relatives than with adoptive family members [1]. In twin studies, differences in concordance between genetically identical and fraternal twins also support heritability for vulnerability to addictions [3,[6][7][8][9][10][11][12]. Twin data allows quantitation of the amount, about 50%, of ad...

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“…Modern laboratory methods of precise sample aliquotting and DNA quantification, along with robust genotyping platforms and novel, validated statistical methods, allow for remarkably accurate estimates of allele frequency differences in cases and controls. [5][6][7] Confirmation by individual genotyping assures that positive results do not reflect error introduced by the pooling procedures. DNA pooling studies allow for the efficient screening of multiple independent samples within the same experiment, increasing the likelihood that the results obtained reflect important risk alleles, rather than spurious signals or artifacts of multiple testing.…”

Section: Introductionmentioning

confidence: 99%

A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder

et al. 2007

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The genetic basis of bipolar disorder has long been thought to be complex, with the potential involvement of multiple genes, but methods to analyze populations with respect to this complexity have only recently become available. We have carried out a genome-wide association study of bipolar disorder by genotyping over 550 000 single-nucleotide polymorphisms (SNPs) in two independent case-control samples of European origin. The initial association screen was performed using pooled DNA, and selected SNPs were confirmed by individual genotyping. While DNA pooling reduces power to detect genetic associations, there is a substantial cost saving and gain in efficiency. A total of 88 SNPs, representing 80 different genes, met the prior criteria for replication in both samples. Effect sizes were modest: no single SNP of large effect was detected. Of 37 SNPs selected for individual genotyping, the strongest association signal was detected at a marker within the first intron of diacylglycerol kinase eta (DGKH; P = 1.5 Â 10 À8 , experiment-wide P < 0.01, OR = 1.59). This gene encodes DGKH, a key protein in the lithium-sensitive phosphatidyl inositol pathway. This first genome-wide association study of bipolar disorder shows that several genes, each of modest effect, reproducibly influence disease risk. Bipolar disorder may be a polygenic disease.

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Identification of the Genetic Basis for Complex Disorders by Use of Pooling-Based Genomewide Single-Nucleotide–Polymorphism Association Studies

Cited by 140 publications

References 50 publications

Familial and genetic risk of transitional cell carcinoma of the urinary tract

Familial and genetic risk of transitional cell carcinoma of the urinary tract

“Higher order” addiction molecular genetics: Convergent data from genome-wide association in humans and mice

A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder

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