Analysis of variation in expression of autosomal dominant osteopetrosis type 2: Searching for modifier genes

Kang Chu, Daniel L. Koller, Richard Snyder, Tonya Fishburn, Dongbing Lai, Steven G. Waguespack, Tatiana Foroud, Michael Econs

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Introduction: Autosomal Dominant Osteopetrosis type II (ADO2) is a heritable osteosclerotic disorder that results from heterozygous mutations in the ClCN7 gene. Analysis of ADO2 in our pedigrees indicates that the penetrance is 66%, with a highly variable phenotype. Methods: To identify genes that modify disease status, we performed a 10 cM genome-wide scan using 400 microsatellite markers in 112 subjects from our 8 largest ADO2 families with mutations in the ClCN7 gene. Results were analyzed by parametric linkage analysis using autosomal dominant and recessive models for affects on disease status. Follow-up genotyping with additional microsatellite markers was performed for regions with LOD scores over 1.5. In addition, we compared the frequency of two nonsynonymous SNPs, rs12926089 (V418M) and rs11559208 (K691E), and one promoter SNP rs960467 in the normal ClCN7 allele between a sample of unaffected gene carriers and clinically affected subjects to test the hypothesis that genetic variation in the non-disease allele within the ClCN7 gene might influence disease expression. Results: We found potential evidence of linkage for a modifier gene(s) on 9q21-22 with a LOD score of 1.89, which is not statistically significant, but interesting. We also found that, for SNP V418M on the non-disease allele with the wild-type ClCN7 sequence, 94.92% (56/59) of clinically affected subjects and 78.13% (25/32) of unaffected gene carriers had a valine while 5.08% (3/59) of the affected subjects and 21.88% (7/32) of unaffected gene carriers had a methionine (P < 0.03). Unfortunately, SNP K691E was not informative in our families. For SNP rs960467, on the non-disease allele with the wild-type ClCN7 gene, 87.93% (51/58) of clinically affected subjects and 62.50% (20/32) of unaffected gene carriers had a C allele while 12.07% (7/58) of the clinically affected subjects and 37.50% (12/32) of unaffected gene carriers had a T allele (P < 0.007). As expected, the polymorphisms on the disease allele were not associated with disease status. Conclusions: Chromosome 9q21-22 may harbor a modifier gene(s) that affect(s) ADO2 disease status and severity. Additionally, we find the associations between the polymorphisms on the non-disease allele and unaffected gene carrier status.

Original languageEnglish
Pages (from-to)655-661
Number of pages7
JournalBone
Volume37
Issue number5
DOIs
StatePublished - Nov 2005

Fingerprint

Modifier Genes
Osteopetrosis
Alleles
Genes
Single Nucleotide Polymorphism
Microsatellite Repeats
Chromosomes, Human, Pair 22
Mutation
Penetrance
Valine
Pedigree
Methionine

Keywords

  • Association
  • Genetic linkage
  • Modifier gene
  • Osteopetrosis
  • Polymorphisms

ASJC Scopus subject areas

  • Physiology
  • Hematology

Cite this

Analysis of variation in expression of autosomal dominant osteopetrosis type 2 : Searching for modifier genes. / Chu, Kang; Koller, Daniel L.; Snyder, Richard; Fishburn, Tonya; Lai, Dongbing; Waguespack, Steven G.; Foroud, Tatiana; Econs, Michael.

In: Bone, Vol. 37, No. 5, 11.2005, p. 655-661.

Research output: Contribution to journalArticle

Chu, Kang ; Koller, Daniel L. ; Snyder, Richard ; Fishburn, Tonya ; Lai, Dongbing ; Waguespack, Steven G. ; Foroud, Tatiana ; Econs, Michael. / Analysis of variation in expression of autosomal dominant osteopetrosis type 2 : Searching for modifier genes. In: Bone. 2005 ; Vol. 37, No. 5. pp. 655-661.
@article{d0fc1262ac4742a1915ae128d0ee0312,
title = "Analysis of variation in expression of autosomal dominant osteopetrosis type 2: Searching for modifier genes",
abstract = "Introduction: Autosomal Dominant Osteopetrosis type II (ADO2) is a heritable osteosclerotic disorder that results from heterozygous mutations in the ClCN7 gene. Analysis of ADO2 in our pedigrees indicates that the penetrance is 66{\%}, with a highly variable phenotype. Methods: To identify genes that modify disease status, we performed a 10 cM genome-wide scan using 400 microsatellite markers in 112 subjects from our 8 largest ADO2 families with mutations in the ClCN7 gene. Results were analyzed by parametric linkage analysis using autosomal dominant and recessive models for affects on disease status. Follow-up genotyping with additional microsatellite markers was performed for regions with LOD scores over 1.5. In addition, we compared the frequency of two nonsynonymous SNPs, rs12926089 (V418M) and rs11559208 (K691E), and one promoter SNP rs960467 in the normal ClCN7 allele between a sample of unaffected gene carriers and clinically affected subjects to test the hypothesis that genetic variation in the non-disease allele within the ClCN7 gene might influence disease expression. Results: We found potential evidence of linkage for a modifier gene(s) on 9q21-22 with a LOD score of 1.89, which is not statistically significant, but interesting. We also found that, for SNP V418M on the non-disease allele with the wild-type ClCN7 sequence, 94.92{\%} (56/59) of clinically affected subjects and 78.13{\%} (25/32) of unaffected gene carriers had a valine while 5.08{\%} (3/59) of the affected subjects and 21.88{\%} (7/32) of unaffected gene carriers had a methionine (P < 0.03). Unfortunately, SNP K691E was not informative in our families. For SNP rs960467, on the non-disease allele with the wild-type ClCN7 gene, 87.93{\%} (51/58) of clinically affected subjects and 62.50{\%} (20/32) of unaffected gene carriers had a C allele while 12.07{\%} (7/58) of the clinically affected subjects and 37.50{\%} (12/32) of unaffected gene carriers had a T allele (P < 0.007). As expected, the polymorphisms on the disease allele were not associated with disease status. Conclusions: Chromosome 9q21-22 may harbor a modifier gene(s) that affect(s) ADO2 disease status and severity. Additionally, we find the associations between the polymorphisms on the non-disease allele and unaffected gene carrier status.",
keywords = "Association, Genetic linkage, Modifier gene, Osteopetrosis, Polymorphisms",
author = "Kang Chu and Koller, {Daniel L.} and Richard Snyder and Tonya Fishburn and Dongbing Lai and Waguespack, {Steven G.} and Tatiana Foroud and Michael Econs",
year = "2005",
month = "11",
doi = "10.1016/j.bone.2005.06.003",
language = "English",
volume = "37",
pages = "655--661",
journal = "Bone",
issn = "8756-3282",
publisher = "Elsevier Inc.",
number = "5",

}

TY - JOUR

T1 - Analysis of variation in expression of autosomal dominant osteopetrosis type 2

T2 - Searching for modifier genes

AU - Chu, Kang

AU - Koller, Daniel L.

AU - Snyder, Richard

AU - Fishburn, Tonya

AU - Lai, Dongbing

AU - Waguespack, Steven G.

AU - Foroud, Tatiana

AU - Econs, Michael

PY - 2005/11

Y1 - 2005/11

N2 - Introduction: Autosomal Dominant Osteopetrosis type II (ADO2) is a heritable osteosclerotic disorder that results from heterozygous mutations in the ClCN7 gene. Analysis of ADO2 in our pedigrees indicates that the penetrance is 66%, with a highly variable phenotype. Methods: To identify genes that modify disease status, we performed a 10 cM genome-wide scan using 400 microsatellite markers in 112 subjects from our 8 largest ADO2 families with mutations in the ClCN7 gene. Results were analyzed by parametric linkage analysis using autosomal dominant and recessive models for affects on disease status. Follow-up genotyping with additional microsatellite markers was performed for regions with LOD scores over 1.5. In addition, we compared the frequency of two nonsynonymous SNPs, rs12926089 (V418M) and rs11559208 (K691E), and one promoter SNP rs960467 in the normal ClCN7 allele between a sample of unaffected gene carriers and clinically affected subjects to test the hypothesis that genetic variation in the non-disease allele within the ClCN7 gene might influence disease expression. Results: We found potential evidence of linkage for a modifier gene(s) on 9q21-22 with a LOD score of 1.89, which is not statistically significant, but interesting. We also found that, for SNP V418M on the non-disease allele with the wild-type ClCN7 sequence, 94.92% (56/59) of clinically affected subjects and 78.13% (25/32) of unaffected gene carriers had a valine while 5.08% (3/59) of the affected subjects and 21.88% (7/32) of unaffected gene carriers had a methionine (P < 0.03). Unfortunately, SNP K691E was not informative in our families. For SNP rs960467, on the non-disease allele with the wild-type ClCN7 gene, 87.93% (51/58) of clinically affected subjects and 62.50% (20/32) of unaffected gene carriers had a C allele while 12.07% (7/58) of the clinically affected subjects and 37.50% (12/32) of unaffected gene carriers had a T allele (P < 0.007). As expected, the polymorphisms on the disease allele were not associated with disease status. Conclusions: Chromosome 9q21-22 may harbor a modifier gene(s) that affect(s) ADO2 disease status and severity. Additionally, we find the associations between the polymorphisms on the non-disease allele and unaffected gene carrier status.

AB - Introduction: Autosomal Dominant Osteopetrosis type II (ADO2) is a heritable osteosclerotic disorder that results from heterozygous mutations in the ClCN7 gene. Analysis of ADO2 in our pedigrees indicates that the penetrance is 66%, with a highly variable phenotype. Methods: To identify genes that modify disease status, we performed a 10 cM genome-wide scan using 400 microsatellite markers in 112 subjects from our 8 largest ADO2 families with mutations in the ClCN7 gene. Results were analyzed by parametric linkage analysis using autosomal dominant and recessive models for affects on disease status. Follow-up genotyping with additional microsatellite markers was performed for regions with LOD scores over 1.5. In addition, we compared the frequency of two nonsynonymous SNPs, rs12926089 (V418M) and rs11559208 (K691E), and one promoter SNP rs960467 in the normal ClCN7 allele between a sample of unaffected gene carriers and clinically affected subjects to test the hypothesis that genetic variation in the non-disease allele within the ClCN7 gene might influence disease expression. Results: We found potential evidence of linkage for a modifier gene(s) on 9q21-22 with a LOD score of 1.89, which is not statistically significant, but interesting. We also found that, for SNP V418M on the non-disease allele with the wild-type ClCN7 sequence, 94.92% (56/59) of clinically affected subjects and 78.13% (25/32) of unaffected gene carriers had a valine while 5.08% (3/59) of the affected subjects and 21.88% (7/32) of unaffected gene carriers had a methionine (P < 0.03). Unfortunately, SNP K691E was not informative in our families. For SNP rs960467, on the non-disease allele with the wild-type ClCN7 gene, 87.93% (51/58) of clinically affected subjects and 62.50% (20/32) of unaffected gene carriers had a C allele while 12.07% (7/58) of the clinically affected subjects and 37.50% (12/32) of unaffected gene carriers had a T allele (P < 0.007). As expected, the polymorphisms on the disease allele were not associated with disease status. Conclusions: Chromosome 9q21-22 may harbor a modifier gene(s) that affect(s) ADO2 disease status and severity. Additionally, we find the associations between the polymorphisms on the non-disease allele and unaffected gene carrier status.

KW - Association

KW - Genetic linkage

KW - Modifier gene

KW - Osteopetrosis

KW - Polymorphisms

UR - http://www.scopus.com/inward/record.url?scp=26944474402&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=26944474402&partnerID=8YFLogxK

U2 - 10.1016/j.bone.2005.06.003

DO - 10.1016/j.bone.2005.06.003

M3 - Article

C2 - 16120485

AN - SCOPUS:26944474402

VL - 37

SP - 655

EP - 661

JO - Bone

JF - Bone

SN - 8756-3282

IS - 5

ER -