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Article: Modifier gene study of meconium ileus in cystic fibrosis: Statistical considerations and gene mapping results

TitleModifier gene study of meconium ileus in cystic fibrosis: Statistical considerations and gene mapping results
Authors
Issue Date2009
PublisherSpringer Verlag. The Journal's web site is located at http://link.springer.de/link/service/journals/00439/index.htm
Citation
Human Genetics, 2009, v. 126 n. 6, p. 763-778 How to Cite?
AbstractCystic fibrosis (CF) is a monogenic disease due to mutations in the CFTR gene. Yet, variability in CF disease presentation is presumed to be affected by modifier genes, such as those recently demonstrated for the pulmonary aspect. Here, we conduct a modifier gene study for meconium ileus (MI), an intestinal obstruction that occurs in 16-20% of CF newborns, providing linkage and association results from large family and case-control samples. Linkage analysis of modifier traits is different than linkage analysis of primary traits on which a sample was ascertained. Here, we articulate a source of confounding unique to modifier gene studies and provide an example of how one might overcome the confounding in the context of linkage studies. Our linkage analysis provided evidence of a MI locus on chromosome 12p13.3, which was segregating in up to 80% of MI families with at least one affected offspring (HLOD = 2.9). Fine mapping of the 12p13.3 region in a large case-control sample of pancreatic insufficient Canadian CF patients with and without MI pointed to the involvement of ADIPOR2 in MI (p = 0.002). This marker was substantially out of Hardy-Weinberg equilibrium in the cases only, and provided evidence of a cohort effect. The association with rs9300298 in the ADIPOR2 gene at the 12p13.3 locus was replicated in an independent sample of CF families. A protective locus, using the phenotype of no-MI, mapped to 4q13.3 (HLOD = 3.19), with substantial heterogeneity. A candidate gene in the region, SLC4A4, provided preliminary evidence of association (p = 0.002), warranting further follow-up studies. Our linkage approach was used to direct our fine-mapping studies, which uncovered two potential modifier genes worthy of follow-up. © 2009 Springer-Verlag.
Persistent Identifierhttp://hdl.handle.net/10722/143355
ISSN
2014 Impact Factor: 4.824
2014 SCImago Journal Rankings: 2.261
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Genome Canada through the Ontario Genomics Institute2004-OGI-3-05
Canadian Cystic Fibrosis Foundation
Ontario Research Fund
NIHHG-0004314
Natural Sciences and Engineering Research Council
Canadian Institutes of Health Research
Ontario Women's Health Council
VZFNM00064203
Funding Information:

This project was supported by Genome Canada through the Ontario Genomics Institute per research agreement 2004-OGI-3-05, by the Canadian Cystic Fibrosis Foundation, by the Ontario Research Fund-Research Excellence Program. L.J. Strug is supported by the NIH (HG-0004314) and the Natural Sciences and Engineering Research Council. R. Dorfman was supported by the joint Fellowship of Canadian Institutes of Health Research and Ontario Women's Health Council. Support by VZFNM00064203 to Milan Macek. The authors express gratitude to all CF patients and their families for participating in this study. The authors thank Nicole Anderson, Jennifer Breaton, Mary Cristofi, Roxanne Rousseau, and Michael Van Spall for their exceptional effort in recruiting and ascertaining Canadian CF families for the study, as well Drs. Miroslava Balascakova, Vera Vavrova and Dana Zemkova for provision of patients with MI. The authors are indebted to the following individuals from member institutions of the Canadian Consortium for CF Genetic Studies for ascertaining patient data and blood samples from CF patients and their families: S. Aaron, P. Barrett, B. Beaurivage, Y. Berthiaume, P. Bigonesse, M. Boland, L. Boucher, J. Boucher, S. Bourgh, F. Brosseau, N.E. Brown, C. Brunoro, N. Bureau, A. Cantin, L. Charette, G. Cote, A. Dale, G. Davidson, K. Devesceri, R. Dicaire, V. Fauvel, A. Freitag, D. N. Garey, M. Gaul, W. Gervais, J. Gjevre, F. Gosse, A. Gravelle, B. Habbick, R. Hennessey, S. B. Holmes, J. Hopkins, D. Hughes, M. Jackson, J. Jacob, A. Jeanneret, P. Kean, W. Kepron, T. Kovesi, V. J. Kumar, L. Lands, M. LaPerriere, J. Leong, R. Levesque, D. Lougheed, M. Lowe, B. Lyttle, K. Malhotra, J. E. Marcotte, S. Marsolais, C. Martineau, E. Matouk, D. McCulloch, R. T. Michael, M. Montgomery, R. Morris, E. M. Nakielna, F. Paquet, H. Pasterkamp, N. Patterson, L. Pedder, L. Peterson, N. Petit, C. Piche, M. Plante, H. R. Rabin, K. Ramlall, F. Raymong, L. Rivard, G. Rivard, M. Roussin, M. Ruel, J. Salgado, L. Semple, E. Sheppard, F. Simard, A. Smith, M. Solomon, R. Stackhouse, J. Tabak, L. Taylor, A. Tsang, E. Tullis, C. Turtle, K. Vandamheen, M. van Spall, R. van Wylick, I. Waters, T. Wells, S. Wiltse, and P. Zuberbuhler.

References

 

DC FieldValueLanguage
dc.contributor.authorDorfman, Ren_HK
dc.contributor.authorLi, Wen_HK
dc.contributor.authorSun, Len_HK
dc.contributor.authorLin, Fen_HK
dc.contributor.authorWang, Yen_HK
dc.contributor.authorSandford, Aen_HK
dc.contributor.authorParé, PDen_HK
dc.contributor.authorMcKay, Ken_HK
dc.contributor.authorKayserova, Hen_HK
dc.contributor.authorPiskackova, Ten_HK
dc.contributor.authorMacEk, Men_HK
dc.contributor.authorCzerska, Ken_HK
dc.contributor.authorSands, Den_HK
dc.contributor.authorTiddens, Hen_HK
dc.contributor.authorMargarit, Sen_HK
dc.contributor.authorRepetto, Gen_HK
dc.contributor.authorSontag, MKen_HK
dc.contributor.authorAccurso, FJen_HK
dc.contributor.authorBlackman, Sen_HK
dc.contributor.authorCutting, GRen_HK
dc.contributor.authorTsui, LCen_HK
dc.contributor.authorCorey, Men_HK
dc.contributor.authorDurie, Pen_HK
dc.contributor.authorZielenski, Jen_HK
dc.contributor.authorStrug, LJen_HK
dc.date.accessioned2011-11-24T09:07:03Z-
dc.date.available2011-11-24T09:07:03Z-
dc.date.issued2009en_HK
dc.identifier.citationHuman Genetics, 2009, v. 126 n. 6, p. 763-778en_HK
dc.identifier.issn0340-6717en_HK
dc.identifier.urihttp://hdl.handle.net/10722/143355-
dc.description.abstractCystic fibrosis (CF) is a monogenic disease due to mutations in the CFTR gene. Yet, variability in CF disease presentation is presumed to be affected by modifier genes, such as those recently demonstrated for the pulmonary aspect. Here, we conduct a modifier gene study for meconium ileus (MI), an intestinal obstruction that occurs in 16-20% of CF newborns, providing linkage and association results from large family and case-control samples. Linkage analysis of modifier traits is different than linkage analysis of primary traits on which a sample was ascertained. Here, we articulate a source of confounding unique to modifier gene studies and provide an example of how one might overcome the confounding in the context of linkage studies. Our linkage analysis provided evidence of a MI locus on chromosome 12p13.3, which was segregating in up to 80% of MI families with at least one affected offspring (HLOD = 2.9). Fine mapping of the 12p13.3 region in a large case-control sample of pancreatic insufficient Canadian CF patients with and without MI pointed to the involvement of ADIPOR2 in MI (p = 0.002). This marker was substantially out of Hardy-Weinberg equilibrium in the cases only, and provided evidence of a cohort effect. The association with rs9300298 in the ADIPOR2 gene at the 12p13.3 locus was replicated in an independent sample of CF families. A protective locus, using the phenotype of no-MI, mapped to 4q13.3 (HLOD = 3.19), with substantial heterogeneity. A candidate gene in the region, SLC4A4, provided preliminary evidence of association (p = 0.002), warranting further follow-up studies. Our linkage approach was used to direct our fine-mapping studies, which uncovered two potential modifier genes worthy of follow-up. © 2009 Springer-Verlag.en_HK
dc.languageeng-
dc.publisherSpringer Verlag. The Journal's web site is located at http://link.springer.de/link/service/journals/00439/index.htmen_HK
dc.relation.ispartofHuman Geneticsen_HK
dc.rightsThe original publication is available at www.springerlink.com-
dc.subject.meshChromosome Mapping-
dc.subject.meshChromosomes, Human, Pair 12-
dc.subject.meshCystic Fibrosis - genetics-
dc.subject.meshIleus - genetics-
dc.subject.meshMeconium-
dc.titleModifier gene study of meconium ileus in cystic fibrosis: Statistical considerations and gene mapping resultsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0340-6717&volume=126&issue=6&spage=763&epage=778&date=2009&atitle=Modifier+gene+study+of+meconium+ileus+in+cystic+fibrosis:+statistical+considerations+and+gene+mapping+results-
dc.identifier.emailTsui, LC: tsuilc@hkucc.hku.hken_HK
dc.identifier.authorityTsui, LC=rp00058en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1007/s00439-009-0724-8en_HK
dc.identifier.pmid19662435en_HK
dc.identifier.pmcidPMC2888886-
dc.identifier.scopuseid_2-s2.0-71349088574en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-71349088574&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume126en_HK
dc.identifier.issue6en_HK
dc.identifier.spage763en_HK
dc.identifier.epage778en_HK
dc.identifier.isiWOS:000271924900004-
dc.publisher.placeGermanyen_HK
dc.identifier.scopusauthoridDorfman, R=8934686800en_HK
dc.identifier.scopusauthoridLi, W=35332556700en_HK
dc.identifier.scopusauthoridSun, L=8601648400en_HK
dc.identifier.scopusauthoridLin, F=35332617400en_HK
dc.identifier.scopusauthoridWang, Y=35076768800en_HK
dc.identifier.scopusauthoridSandford, A=7006552245en_HK
dc.identifier.scopusauthoridParé, PD=7103044327en_HK
dc.identifier.scopusauthoridMcKay, K=35584906000en_HK
dc.identifier.scopusauthoridKayserova, H=6602313031en_HK
dc.identifier.scopusauthoridPiskackova, T=15756500700en_HK
dc.identifier.scopusauthoridMacEk, M=35332282600en_HK
dc.identifier.scopusauthoridCzerska, K=6506799549en_HK
dc.identifier.scopusauthoridSands, D=7101686401en_HK
dc.identifier.scopusauthoridTiddens, H=7004464192en_HK
dc.identifier.scopusauthoridMargarit, S=35226462000en_HK
dc.identifier.scopusauthoridRepetto, G=7007008546en_HK
dc.identifier.scopusauthoridSontag, MK=7003500210en_HK
dc.identifier.scopusauthoridAccurso, FJ=7005853455en_HK
dc.identifier.scopusauthoridBlackman, S=14824786900en_HK
dc.identifier.scopusauthoridCutting, GR=7006007820en_HK
dc.identifier.scopusauthoridTsui, LC=7102754167en_HK
dc.identifier.scopusauthoridCorey, M=7005819978en_HK
dc.identifier.scopusauthoridDurie, P=7005360997en_HK
dc.identifier.scopusauthoridZielenski, J=7003732699en_HK
dc.identifier.scopusauthoridStrug, LJ=6602663170en_HK
dc.identifier.citeulike5543552-

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