Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study

Todd E. Druley; Lihua Wang; Shiow J. Lin; Joseph H. Lee; Qunyuan Zhang; E. Warwick Daw; Haley J. Abel; Sara E. Chasnoff; Enrique I. Ramos; Benjamin T. Levinson; Bharat Thyagarajan; Anne B. Newman; Kaare Christensen; Richard Mayeux; Michael A. Province

doi:10.1186/s12877-016-0253-y

Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study

Todd E. Druley, Lihua Wang, Shiow J. Lin, Joseph H. Lee, Qunyuan Zhang, E. Warwick Daw, Haley J. Abel, Sara E. Chasnoff, Enrique I. Ramos, Benjamin T. Levinson, Bharat Thyagarajan, Anne B. Newman, Kaare Christensen, Richard Mayeux, Michael A. Province

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

Background: The Long Life Family Study (LLFS) is an international study to identify the genetic components of various healthy aging phenotypes. We hypothesized that pedigree-specific rare variants at longevity-associated genes could have a similar functional impact on healthy phenotypes. Methods: We performed custom hybridization capture sequencing to identify the functional variants in 464 candidate genes for longevity or the major diseases of aging in 615 pedigrees (4,953 individuals) from the LLFS, using a multiplexed, custom hybridization capture. Variants were analyzed individually or as a group across an entire gene for association to aging phenotypes using family based tests. Results: We found significant associations to three genes and nine single variants. Most notably, we found a novel variant significantly associated with exceptional survival in the 3' UTR OBFC1 in 13 individuals from six pedigrees. OBFC1 (chromosome 10) is involved in telomere maintenance, and falls within a linkage peak recently reported from an analysis of telomere length in LLFS families. Two different algorithms for single gene associations identified three genes with an enrichment of variation that was significantly associated with three phenotypes (GSK3B with the Healthy Aging Index, NOTCH1 with diastolic blood pressure and TP53 with serum HDL). Conclusions: Sequencing analysis of family-based associations for age-related phenotypes can identify rare or novel variants.

Original language	English (US)
Article number	80
Journal	BMC Geriatrics
Volume	16
Issue number	1
DOIs	https://doi.org/10.1186/s12877-016-0253-y
State	Published - Apr 9 2016

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health, National Institute of Aging [U01 AG023746 (The Long Life Family Study)]. We would like to thank W. Rossi and E. Hadley for helpful discussions. We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for next-generation sequencing. The Center is partially supported by NCI Cancer Center Support Grant P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant UL1RR024992 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH.

Publisher Copyright:
© 2016 Druley et al.

Keywords

Aging
Family
Genetics
Genomics
Geriatrics
Pedigrees
Sequencing

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10.1186/s12877-016-0253-y

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Druley, T. E., Wang, L., Lin, S. J., Lee, J. H., Zhang, Q., Daw, E. W., Abel, H. J., Chasnoff, S. E., Ramos, E. I., Levinson, B. T., Thyagarajan, B., Newman, A. B., Christensen, K., Mayeux, R., & Province, M. A. (2016). Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study. BMC Geriatrics, 16(1), [80]. https://doi.org/10.1186/s12877-016-0253-y

Druley, TE, Wang, L, Lin, SJ, Lee, JH, Zhang, Q, Daw, EW, Abel, HJ, Chasnoff, SE, Ramos, EI, Levinson, BT, Thyagarajan, B, Newman, AB, Christensen, K, Mayeux, R & Province, MA 2016, 'Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study', BMC Geriatrics, vol. 16, no. 1, 80. https://doi.org/10.1186/s12877-016-0253-y

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title = "Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study",

abstract = "Background: The Long Life Family Study (LLFS) is an international study to identify the genetic components of various healthy aging phenotypes. We hypothesized that pedigree-specific rare variants at longevity-associated genes could have a similar functional impact on healthy phenotypes. Methods: We performed custom hybridization capture sequencing to identify the functional variants in 464 candidate genes for longevity or the major diseases of aging in 615 pedigrees (4,953 individuals) from the LLFS, using a multiplexed, custom hybridization capture. Variants were analyzed individually or as a group across an entire gene for association to aging phenotypes using family based tests. Results: We found significant associations to three genes and nine single variants. Most notably, we found a novel variant significantly associated with exceptional survival in the 3' UTR OBFC1 in 13 individuals from six pedigrees. OBFC1 (chromosome 10) is involved in telomere maintenance, and falls within a linkage peak recently reported from an analysis of telomere length in LLFS families. Two different algorithms for single gene associations identified three genes with an enrichment of variation that was significantly associated with three phenotypes (GSK3B with the Healthy Aging Index, NOTCH1 with diastolic blood pressure and TP53 with serum HDL). Conclusions: Sequencing analysis of family-based associations for age-related phenotypes can identify rare or novel variants.",

keywords = "Aging, Family, Genetics, Genomics, Geriatrics, Pedigrees, Sequencing",

author = "Druley, {Todd E.} and Lihua Wang and Lin, {Shiow J.} and Lee, {Joseph H.} and Qunyuan Zhang and Daw, {E. Warwick} and Abel, {Haley J.} and Chasnoff, {Sara E.} and Ramos, {Enrique I.} and Levinson, {Benjamin T.} and Bharat Thyagarajan and Newman, {Anne B.} and Kaare Christensen and Richard Mayeux and Province, {Michael A.}",

note = "Funding Information: This work was supported by the National Institutes of Health, National Institute of Aging [U01 AG023746 (The Long Life Family Study)]. We would like to thank W. Rossi and E. Hadley for helpful discussions. We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for next-generation sequencing. The Center is partially supported by NCI Cancer Center Support Grant P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant UL1RR024992 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. Publisher Copyright: {\textcopyright} 2016 Druley et al.",

year = "2016",

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doi = "10.1186/s12877-016-0253-y",

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T1 - Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study

AU - Druley, Todd E.

AU - Wang, Lihua

AU - Lin, Shiow J.

AU - Lee, Joseph H.

AU - Zhang, Qunyuan

AU - Daw, E. Warwick

AU - Abel, Haley J.

AU - Chasnoff, Sara E.

AU - Ramos, Enrique I.

AU - Levinson, Benjamin T.

AU - Thyagarajan, Bharat

AU - Newman, Anne B.

AU - Christensen, Kaare

AU - Mayeux, Richard

AU - Province, Michael A.

N1 - Funding Information: This work was supported by the National Institutes of Health, National Institute of Aging [U01 AG023746 (The Long Life Family Study)]. We would like to thank W. Rossi and E. Hadley for helpful discussions. We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for next-generation sequencing. The Center is partially supported by NCI Cancer Center Support Grant P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant UL1RR024992 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. Publisher Copyright: © 2016 Druley et al.

PY - 2016/4/9

Y1 - 2016/4/9

N2 - Background: The Long Life Family Study (LLFS) is an international study to identify the genetic components of various healthy aging phenotypes. We hypothesized that pedigree-specific rare variants at longevity-associated genes could have a similar functional impact on healthy phenotypes. Methods: We performed custom hybridization capture sequencing to identify the functional variants in 464 candidate genes for longevity or the major diseases of aging in 615 pedigrees (4,953 individuals) from the LLFS, using a multiplexed, custom hybridization capture. Variants were analyzed individually or as a group across an entire gene for association to aging phenotypes using family based tests. Results: We found significant associations to three genes and nine single variants. Most notably, we found a novel variant significantly associated with exceptional survival in the 3' UTR OBFC1 in 13 individuals from six pedigrees. OBFC1 (chromosome 10) is involved in telomere maintenance, and falls within a linkage peak recently reported from an analysis of telomere length in LLFS families. Two different algorithms for single gene associations identified three genes with an enrichment of variation that was significantly associated with three phenotypes (GSK3B with the Healthy Aging Index, NOTCH1 with diastolic blood pressure and TP53 with serum HDL). Conclusions: Sequencing analysis of family-based associations for age-related phenotypes can identify rare or novel variants.

AB - Background: The Long Life Family Study (LLFS) is an international study to identify the genetic components of various healthy aging phenotypes. We hypothesized that pedigree-specific rare variants at longevity-associated genes could have a similar functional impact on healthy phenotypes. Methods: We performed custom hybridization capture sequencing to identify the functional variants in 464 candidate genes for longevity or the major diseases of aging in 615 pedigrees (4,953 individuals) from the LLFS, using a multiplexed, custom hybridization capture. Variants were analyzed individually or as a group across an entire gene for association to aging phenotypes using family based tests. Results: We found significant associations to three genes and nine single variants. Most notably, we found a novel variant significantly associated with exceptional survival in the 3' UTR OBFC1 in 13 individuals from six pedigrees. OBFC1 (chromosome 10) is involved in telomere maintenance, and falls within a linkage peak recently reported from an analysis of telomere length in LLFS families. Two different algorithms for single gene associations identified three genes with an enrichment of variation that was significantly associated with three phenotypes (GSK3B with the Healthy Aging Index, NOTCH1 with diastolic blood pressure and TP53 with serum HDL). Conclusions: Sequencing analysis of family-based associations for age-related phenotypes can identify rare or novel variants.

KW - Aging

KW - Family

KW - Genetics

KW - Genomics

KW - Geriatrics

KW - Pedigrees

KW - Sequencing

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Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study

Abstract

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