Whole-exome sequencing identifies the 6q12-q16 linkage region and a candidate gene, TTK, for pulmonary nontuberculous mycobacterial disease

Fei Chen, Eva P. Szymanski, Kenneth N. Olivier, Xinyue Liu, Hervé Tettelin, Steven M. Holland, Priya Duggal

Research output: Contribution to journalArticle

Abstract

Rationale: Pulmonary nontuberculous mycobacterial disease (PNTM) often affects white postmenopausal women, with a tall and lean body habitus and higher rates of scoliosis, pectus excavatum, mitral valve prolapse, and mutations in the CFTR gene. These clinical features and the familial clustering of the disease suggest an underlying genetic mechanism. Objectives: To map the genes associated with PNTM, whole-exome sequencing was conducted in 12 PNTM families and 57 sporadic cases recruited at the National Institutes of Health Clinical Center during 2001-2013. Methods: We performed a variant-level and a gene-level parametric linkage analysis on nine PNTM families (16 affected and 20 unaffected) as well as a gene-level association analysis on nine PNTM families and 55 sporadic cases. Measurements and Main Results: The genome-wide variant-level linkage analysis using 4,328 independent common variants identified a 20-cM region on chromosome 6q12-6q16 (heterogeneity logarithm of odds score = 3.9), under a recessive disease model with 100% penetrance and a risk allele frequency of 5%. All genes on chromosome 6 were then tested in the gene-level linkage analysis, using the collapsed haplotype pattern method. The TTK protein kinase gene (TTK) on chromosome 6q14.1 was the most significant (heterogeneity logarithm of odds score = 3.38). In addition, the genes MAP2K4, RCOR3, KRT83, IFNLR1, and SLC29A1 were associated with PNTM in our gene-level association analysis. Conclusions: The TTK gene encodes a protein kinase that is essential for mitotic checkpoints and the DNA damage response. TTK and other genetic loci identified in our study may contribute to the increased susceptibility to NTM infection and its progression to pulmonary disease.

Original languageEnglish (US)
Pages (from-to)1599-1604
Number of pages6
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume196
Issue number12
DOIs
StatePublished - Dec 15 2017

Fingerprint

Exome
Lung
Genes
Protein Kinases
Chromosomes
M Phase Cell Cycle Checkpoints
Funnel Chest
Mitral Valve Prolapse
Chromosomes, Human, Pair 6
Genetic Loci
Penetrance
National Institutes of Health (U.S.)
Scoliosis
Gene Frequency
Haplotypes
Lung Diseases
DNA Damage
Cluster Analysis
Genome

Keywords

  • DNA sequence analysis
  • Genetic linkage
  • Nontuberculous mycobacteria

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Whole-exome sequencing identifies the 6q12-q16 linkage region and a candidate gene, TTK, for pulmonary nontuberculous mycobacterial disease. / Chen, Fei; Szymanski, Eva P.; Olivier, Kenneth N.; Liu, Xinyue; Tettelin, Hervé; Holland, Steven M.; Duggal, Priya.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 196, No. 12, 15.12.2017, p. 1599-1604.

Research output: Contribution to journalArticle

Chen, Fei ; Szymanski, Eva P. ; Olivier, Kenneth N. ; Liu, Xinyue ; Tettelin, Hervé ; Holland, Steven M. ; Duggal, Priya. / Whole-exome sequencing identifies the 6q12-q16 linkage region and a candidate gene, TTK, for pulmonary nontuberculous mycobacterial disease. In: American Journal of Respiratory and Critical Care Medicine. 2017 ; Vol. 196, No. 12. pp. 1599-1604.
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abstract = "Rationale: Pulmonary nontuberculous mycobacterial disease (PNTM) often affects white postmenopausal women, with a tall and lean body habitus and higher rates of scoliosis, pectus excavatum, mitral valve prolapse, and mutations in the CFTR gene. These clinical features and the familial clustering of the disease suggest an underlying genetic mechanism. Objectives: To map the genes associated with PNTM, whole-exome sequencing was conducted in 12 PNTM families and 57 sporadic cases recruited at the National Institutes of Health Clinical Center during 2001-2013. Methods: We performed a variant-level and a gene-level parametric linkage analysis on nine PNTM families (16 affected and 20 unaffected) as well as a gene-level association analysis on nine PNTM families and 55 sporadic cases. Measurements and Main Results: The genome-wide variant-level linkage analysis using 4,328 independent common variants identified a 20-cM region on chromosome 6q12-6q16 (heterogeneity logarithm of odds score = 3.9), under a recessive disease model with 100{\%} penetrance and a risk allele frequency of 5{\%}. All genes on chromosome 6 were then tested in the gene-level linkage analysis, using the collapsed haplotype pattern method. The TTK protein kinase gene (TTK) on chromosome 6q14.1 was the most significant (heterogeneity logarithm of odds score = 3.38). In addition, the genes MAP2K4, RCOR3, KRT83, IFNLR1, and SLC29A1 were associated with PNTM in our gene-level association analysis. Conclusions: The TTK gene encodes a protein kinase that is essential for mitotic checkpoints and the DNA damage response. TTK and other genetic loci identified in our study may contribute to the increased susceptibility to NTM infection and its progression to pulmonary disease.",
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T1 - Whole-exome sequencing identifies the 6q12-q16 linkage region and a candidate gene, TTK, for pulmonary nontuberculous mycobacterial disease

AU - Chen, Fei

AU - Szymanski, Eva P.

AU - Olivier, Kenneth N.

AU - Liu, Xinyue

AU - Tettelin, Hervé

AU - Holland, Steven M.

AU - Duggal, Priya

PY - 2017/12/15

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N2 - Rationale: Pulmonary nontuberculous mycobacterial disease (PNTM) often affects white postmenopausal women, with a tall and lean body habitus and higher rates of scoliosis, pectus excavatum, mitral valve prolapse, and mutations in the CFTR gene. These clinical features and the familial clustering of the disease suggest an underlying genetic mechanism. Objectives: To map the genes associated with PNTM, whole-exome sequencing was conducted in 12 PNTM families and 57 sporadic cases recruited at the National Institutes of Health Clinical Center during 2001-2013. Methods: We performed a variant-level and a gene-level parametric linkage analysis on nine PNTM families (16 affected and 20 unaffected) as well as a gene-level association analysis on nine PNTM families and 55 sporadic cases. Measurements and Main Results: The genome-wide variant-level linkage analysis using 4,328 independent common variants identified a 20-cM region on chromosome 6q12-6q16 (heterogeneity logarithm of odds score = 3.9), under a recessive disease model with 100% penetrance and a risk allele frequency of 5%. All genes on chromosome 6 were then tested in the gene-level linkage analysis, using the collapsed haplotype pattern method. The TTK protein kinase gene (TTK) on chromosome 6q14.1 was the most significant (heterogeneity logarithm of odds score = 3.38). In addition, the genes MAP2K4, RCOR3, KRT83, IFNLR1, and SLC29A1 were associated with PNTM in our gene-level association analysis. Conclusions: The TTK gene encodes a protein kinase that is essential for mitotic checkpoints and the DNA damage response. TTK and other genetic loci identified in our study may contribute to the increased susceptibility to NTM infection and its progression to pulmonary disease.

AB - Rationale: Pulmonary nontuberculous mycobacterial disease (PNTM) often affects white postmenopausal women, with a tall and lean body habitus and higher rates of scoliosis, pectus excavatum, mitral valve prolapse, and mutations in the CFTR gene. These clinical features and the familial clustering of the disease suggest an underlying genetic mechanism. Objectives: To map the genes associated with PNTM, whole-exome sequencing was conducted in 12 PNTM families and 57 sporadic cases recruited at the National Institutes of Health Clinical Center during 2001-2013. Methods: We performed a variant-level and a gene-level parametric linkage analysis on nine PNTM families (16 affected and 20 unaffected) as well as a gene-level association analysis on nine PNTM families and 55 sporadic cases. Measurements and Main Results: The genome-wide variant-level linkage analysis using 4,328 independent common variants identified a 20-cM region on chromosome 6q12-6q16 (heterogeneity logarithm of odds score = 3.9), under a recessive disease model with 100% penetrance and a risk allele frequency of 5%. All genes on chromosome 6 were then tested in the gene-level linkage analysis, using the collapsed haplotype pattern method. The TTK protein kinase gene (TTK) on chromosome 6q14.1 was the most significant (heterogeneity logarithm of odds score = 3.38). In addition, the genes MAP2K4, RCOR3, KRT83, IFNLR1, and SLC29A1 were associated with PNTM in our gene-level association analysis. Conclusions: The TTK gene encodes a protein kinase that is essential for mitotic checkpoints and the DNA damage response. TTK and other genetic loci identified in our study may contribute to the increased susceptibility to NTM infection and its progression to pulmonary disease.

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KW - Nontuberculous mycobacteria

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