TY - JOUR
T1 - Modifier gene study of meconium ileus in cystic fibrosis
T2 - Statistical considerations and gene mapping results
AU - Dorfman, Ruslan
AU - Li, Weili
AU - Sun, Lei
AU - Lin, Fan
AU - Wang, Yongqian
AU - Sandford, Andrew
AU - Paré, Peter D.
AU - McKay, Karen
AU - Kayserova, Hana
AU - Piskackova, Tereza
AU - MacEk, Milan
AU - Czerska, Kamila
AU - Sands, Dorota
AU - Tiddens, Harm
AU - Margarit, Sonia
AU - Repetto, Gabriela
AU - Sontag, Marci K.
AU - Accurso, Frank J.
AU - Blackman, Scott
AU - Cutting, Garry R.
AU - Tsui, Lap Chee
AU - Corey, Mary
AU - Durie, Peter
AU - Zielenski, Julian
AU - Strug, Lisa J.
N1 - Funding Information:
Acknowledgments 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,
PY - 2009/12
Y1 - 2009/12
N2 - Cystic 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.
AB - Cystic 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.
UR - http://www.scopus.com/inward/record.url?scp=71349088574&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=71349088574&partnerID=8YFLogxK
U2 - 10.1007/s00439-009-0724-8
DO - 10.1007/s00439-009-0724-8
M3 - Article
C2 - 19662435
AN - SCOPUS:71349088574
SN - 0340-6717
VL - 126
SP - 763
EP - 778
JO - Human genetics
JF - Human genetics
IS - 6
ER -