Modifier gene study of meconium ileus in cystic fibrosis: statistical considerations and gene mapping results.
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.
Dorfman
Ruslan
R
Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON, Canada. ruslan.dorfman@gmail.com
Li
Weili
W
Sun
Lei
L
Lin
Fan
F
Wang
Yongqian
Y
Sandford
Andrew
A
Paré
Peter D
PD
McKay
Karen
K
Kayserova
Hana
H
Piskackova
Tereza
T
Macek
Milan
M
Czerska
Kamila
K
Sands
Dorota
D
Tiddens
Harm
H
Margarit
Sonia
S
Repetto
Gabriela
G
Sontag
Marci K
MK
Accurso
Frank J
FJ
Blackman
Scott
S
Cutting
Garry R
GR
Tsui
Lap-Chee
LC
Corey
Mary
M
Durie
Peter
P
Zielenski
Julian
J
Strug
Lisa J
LJ
D000293:Adolescent; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12; D003550:Cystic Fibrosis / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D045823:Ileus / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D008470:Meconium; D054419:Receptors, Adiponectin / Q000235:genetics; D027982:Sodium-Bicarbonate Symporters / Q000235:genetics
C475420:ADIPOR2 protein, human; D054419:Receptors, Adiponectin; C498898:SLC4A4 protein, human; D027982:Sodium-Bicarbonate Symporters