X-linked genes and risk of orofacial clefts: evidence from two population-based studies in Scandinavia

Astanand Jugessur; Øivind Skare; Rolv T Lie; Allen J Wilcox; Kaare Christensen; Lene Christiansen; Truc Trung Nguyen; Jeffrey C Murray; Håkon K Gjessing

doi:10.1371/journal.pone.0039240

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X-linked genes and risk of orofacial clefts: evidence from two population-based studies in Scandinavia

Journal article

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X-linked genes and risk of orofacial clefts: evidence from two population-based studies in Scandinavia

Astanand Jugessur, Øivind Skare, Rolv T Lie, Allen J Wilcox, Kaare Christensen, Lene Christiansen, Truc Trung Nguyen, Jeffrey C Murray and Håkon K Gjessing

PloS one, Vol.7(6), pp.e39240-e39240

2012

DOI: 10.1371/journal.pone.0039240

PMCID: PMC3378529

PMID: 22723972

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Abstract

Orofacial clefts are common birth defects of complex etiology, with an excess of males among babies with cleft lip and palate, and an excess of females among those with cleft palate only. Although genes on the X chromosome have been implicated in clefting, there has been no association analysis of X-linked markers. We added new functionalities in the HAPLIN statistical software to enable association analysis of X-linked markers and an exploration of various causal scenarios relevant to orofacial clefts. Genotypes for 48 SNPs in 18 candidate genes on the X chromosome were analyzed in two population-based samples from Scandinavia (562 Norwegian and 235 Danish case-parent triads). For haplotype analysis, we used a sliding-window approach and assessed isolated cleft lip with or without cleft palate (iCL/P) separately from isolated cleft palate only (iCPO). We tested three statistical models in HAPLIN, allowing for: i) the same relative risk in males and females, ii) sex-specific relative risks, and iii) X-inactivation in females. We found weak but consistent associations with the oral-facial-digital syndrome 1 (OFD1) gene (formerly known as CXORF5) in the Danish iCL/P samples across all models, but not in the Norwegian iCL/P samples. In sex-specific analyses, the association with OFD1 was in male cases only. No analyses showed associations with iCPO in either the Norwegian or the Danish sample. The association of OFD1 with iCL/P is plausible given the biological relevance of this gene. However, the lack of replication in the Norwegian samples highlights the need to verify these preliminary findings in other large datasets. More generally, the novel analytic methods presented here are widely applicable to investigations of the role of X-linked genes in complex traits.

Haplotypes

Genetic Predisposition to Disease

Cleft Lip - epidemiology

Humans

Male

Risk

Cleft Palate - genetics

Cleft Lip - genetics

Genes, X-Linked

Female

Models, Genetic

Polymorphism, Single Nucleotide

Cleft Palate - epidemiology

Scandinavian and Nordic Countries - epidemiology

X Chromosome Inactivation

Details

Title: Subtitle: X-linked genes and risk of orofacial clefts: evidence from two population-based studies in Scandinavia
Creators: Astanand Jugessur - Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway. astanand.jugessur@fhi.no
Øivind Skare
Rolv T Lie
Allen J Wilcox
Kaare Christensen
Lene Christiansen
Truc Trung Nguyen
Jeffrey C Murray
Håkon K Gjessing
Resource Type: Journal article
Publication Details: PloS one, Vol.7(6), pp.e39240-e39240
DOI: 10.1371/journal.pone.0039240
PMID: 22723972
PMCID: PMC3378529
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: N01HG65403 / NHGRI NIH HHS P30 ES005605 / NIEHS NIH HHS Intramural NIH HHS P60 DE13076 / NIDCR NIH HHS R01 DE008559 / NIDCR NIH HHS R37 DE008559 / NIDCR NIH HHS P30 ES05605 / NIEHS NIH HHS DE08559 / NIDCR NIH HHS R01 DE011948 / NIDCR NIH HHS P60 DE013076 / NIDCR NIH HHS R01 DE-11948-04 / NIDCR NIH HHS
Language: English
Date published: 2012
Academic Unit: Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9984025414602771

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