Identification of Novel Alzheimer’s Disease Loci Using Sex-Specific Family-Based Association Analysis of Whole-Genome Sequence Data

Dmitry Prokopenko; Julian Hecker; Rory Kirchner; Brad A. Chapman; Oliver Hoffman; Kristina Mullin; Winston Hide; Lars Bertram; Nan Laird; Dawn L. DeMeo; Christoph Lange; Rudolph E. Tanzi

doi:10.1038/s41598-020-61883-6

Identification of Novel Alzheimer’s Disease Loci Using Sex-Specific Family-Based Association Analysis of Whole-Genome Sequence Data

Dmitry Prokopenko, Julian Hecker, Rory Kirchner, Brad A. Chapman, Oliver Hoffman, Kristina Mullin, Winston Hide, Lars Bertram, Nan Laird, Dawn L. DeMeo, Christoph Lange, Rudolph E. Tanzi^*

^*Corresponding author for this work

Clinic of Rheumatology

32 Citations (Scopus)

Abstract

With the advent of whole genome-sequencing (WGS) studies, family-based designs enable sex-specific analysis approaches that can be applied to only affected individuals; tests using family-based designs are attractive because they are completely robust against the effects of population substructure. These advantages make family-based association tests (FBATs) that use siblings as well as parents especially suited for the analysis of late-onset diseases such as Alzheimer’s Disease (AD). However, the application of FBATs to assess sex-specific effects can require additional filtering steps, as sensitivity to sequencing errors is amplified in this type of analysis. Here, we illustrate the implementation of robust analysis approaches and additional filtering steps that can minimize the chances of false positive-findings due to sex-specific sequencing errors. We apply this approach to two family-based AD datasets and identify four novel loci (GRID1, RIOK3, MCPH1, ZBTB7C) showing sex-specific association with AD risk. Following stringent quality control filtering, the strongest candidate is ZBTB7C (P_inter = 1.83 × 10⁻⁷), in which the minor allele of rs1944572 confers increased risk for AD in females and protection in males. ZBTB7C encodes the Zinc Finger and BTB Domain Containing 7C, a transcriptional repressor of membrane metalloproteases (MMP). Members of this MMP family were implicated in AD neuropathology.

Original language	English
Article number	5029
Journal	Scientific Reports
Volume	10
Issue number	1
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-020-61883-6
Publication status	Published - 01.12.2020

Funding

This work was supported by Cure Alzheimer’s Fund. D.P. was supported by the Women’s Alzheimer’s Movement research grant. D.L.D. was supported by PO1 HL 132825, PO1 HL 114501, PO1 HL 105339. R.K., B.A.C. and O.H. at the Harvard Chan Bioinformatics Core was supported in part by the Harvard NeuroDiscovery Center. The computations in this paper were run in part on the Odyssey cluster supported by the FAS Division of Science, Research Computing Group at Harvard University with support from John Morrissey and in part on compute provided by Dell HPC Research Computing Solutions with support by Glen Otero. The funding body has no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. Please refer to the Supplementary Note for full acknowledgements.

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10.1038/s41598-020-61883-6

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Prokopenko, D., Hecker, J., Kirchner, R., Chapman, B. A., Hoffman, O., Mullin, K., Hide, W., Bertram, L., Laird, N., DeMeo, D. L., Lange, C., & Tanzi, R. E. (2020). Identification of Novel Alzheimer’s Disease Loci Using Sex-Specific Family-Based Association Analysis of Whole-Genome Sequence Data. Scientific Reports, 10(1), Article 5029. https://doi.org/10.1038/s41598-020-61883-6

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title = "Identification of Novel Alzheimer{\textquoteright}s Disease Loci Using Sex-Specific Family-Based Association Analysis of Whole-Genome Sequence Data",

abstract = "With the advent of whole genome-sequencing (WGS) studies, family-based designs enable sex-specific analysis approaches that can be applied to only affected individuals; tests using family-based designs are attractive because they are completely robust against the effects of population substructure. These advantages make family-based association tests (FBATs) that use siblings as well as parents especially suited for the analysis of late-onset diseases such as Alzheimer{\textquoteright}s Disease (AD). However, the application of FBATs to assess sex-specific effects can require additional filtering steps, as sensitivity to sequencing errors is amplified in this type of analysis. Here, we illustrate the implementation of robust analysis approaches and additional filtering steps that can minimize the chances of false positive-findings due to sex-specific sequencing errors. We apply this approach to two family-based AD datasets and identify four novel loci (GRID1, RIOK3, MCPH1, ZBTB7C) showing sex-specific association with AD risk. Following stringent quality control filtering, the strongest candidate is ZBTB7C (Pinter = 1.83 × 10−7), in which the minor allele of rs1944572 confers increased risk for AD in females and protection in males. ZBTB7C encodes the Zinc Finger and BTB Domain Containing 7C, a transcriptional repressor of membrane metalloproteases (MMP). Members of this MMP family were implicated in AD neuropathology.",

author = "Dmitry Prokopenko and Julian Hecker and Rory Kirchner and Chapman, \{Brad A.\} and Oliver Hoffman and Kristina Mullin and Winston Hide and Lars Bertram and Nan Laird and DeMeo, \{Dawn L.\} and Christoph Lange and Tanzi, \{Rudolph E.\}",

note = "Funding Information: This work was supported by Cure Alzheimer{\textquoteright}s Fund. D.P. was supported by the Women{\textquoteright}s Alzheimer{\textquoteright}s Movement research grant. D.L.D. was supported by PO1 HL 132825, PO1 HL 114501, PO1 HL 105339. R.K., B.A.C. and O.H. at the Harvard Chan Bioinformatics Core was supported in part by the Harvard NeuroDiscovery Center. The computations in this paper were run in part on the Odyssey cluster supported by the FAS Division of Science, Research Computing Group at Harvard University with support from John Morrissey and in part on compute provided by Dell HPC Research Computing Solutions with support by Glen Otero. The funding body has no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. Please refer to the Supplementary Note for full acknowledgements. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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doi = "10.1038/s41598-020-61883-6",

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T1 - Identification of Novel Alzheimer’s Disease Loci Using Sex-Specific Family-Based Association Analysis of Whole-Genome Sequence Data

AU - Prokopenko, Dmitry

AU - Hecker, Julian

AU - Kirchner, Rory

AU - Chapman, Brad A.

AU - Hoffman, Oliver

AU - Mullin, Kristina

AU - Hide, Winston

AU - Bertram, Lars

AU - Laird, Nan

AU - DeMeo, Dawn L.

AU - Lange, Christoph

AU - Tanzi, Rudolph E.

N1 - Funding Information: This work was supported by Cure Alzheimer’s Fund. D.P. was supported by the Women’s Alzheimer’s Movement research grant. D.L.D. was supported by PO1 HL 132825, PO1 HL 114501, PO1 HL 105339. R.K., B.A.C. and O.H. at the Harvard Chan Bioinformatics Core was supported in part by the Harvard NeuroDiscovery Center. The computations in this paper were run in part on the Odyssey cluster supported by the FAS Division of Science, Research Computing Group at Harvard University with support from John Morrissey and in part on compute provided by Dell HPC Research Computing Solutions with support by Glen Otero. The funding body has no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. Please refer to the Supplementary Note for full acknowledgements. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - With the advent of whole genome-sequencing (WGS) studies, family-based designs enable sex-specific analysis approaches that can be applied to only affected individuals; tests using family-based designs are attractive because they are completely robust against the effects of population substructure. These advantages make family-based association tests (FBATs) that use siblings as well as parents especially suited for the analysis of late-onset diseases such as Alzheimer’s Disease (AD). However, the application of FBATs to assess sex-specific effects can require additional filtering steps, as sensitivity to sequencing errors is amplified in this type of analysis. Here, we illustrate the implementation of robust analysis approaches and additional filtering steps that can minimize the chances of false positive-findings due to sex-specific sequencing errors. We apply this approach to two family-based AD datasets and identify four novel loci (GRID1, RIOK3, MCPH1, ZBTB7C) showing sex-specific association with AD risk. Following stringent quality control filtering, the strongest candidate is ZBTB7C (Pinter = 1.83 × 10−7), in which the minor allele of rs1944572 confers increased risk for AD in females and protection in males. ZBTB7C encodes the Zinc Finger and BTB Domain Containing 7C, a transcriptional repressor of membrane metalloproteases (MMP). Members of this MMP family were implicated in AD neuropathology.

AB - With the advent of whole genome-sequencing (WGS) studies, family-based designs enable sex-specific analysis approaches that can be applied to only affected individuals; tests using family-based designs are attractive because they are completely robust against the effects of population substructure. These advantages make family-based association tests (FBATs) that use siblings as well as parents especially suited for the analysis of late-onset diseases such as Alzheimer’s Disease (AD). However, the application of FBATs to assess sex-specific effects can require additional filtering steps, as sensitivity to sequencing errors is amplified in this type of analysis. Here, we illustrate the implementation of robust analysis approaches and additional filtering steps that can minimize the chances of false positive-findings due to sex-specific sequencing errors. We apply this approach to two family-based AD datasets and identify four novel loci (GRID1, RIOK3, MCPH1, ZBTB7C) showing sex-specific association with AD risk. Following stringent quality control filtering, the strongest candidate is ZBTB7C (Pinter = 1.83 × 10−7), in which the minor allele of rs1944572 confers increased risk for AD in females and protection in males. ZBTB7C encodes the Zinc Finger and BTB Domain Containing 7C, a transcriptional repressor of membrane metalloproteases (MMP). Members of this MMP family were implicated in AD neuropathology.

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JF - Scientific Reports

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ER -

Identification of Novel Alzheimer’s Disease Loci Using Sex-Specific Family-Based Association Analysis of Whole-Genome Sequence Data

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