Segregation of a rare TTC3 variant in an extended family with late-onset Alzheimer disease

Martin A. Kohli, Holly N Cukier, Kara L. Hamilton-Nelson, Sophie Rolati, Brian W. Kunkle, Patrice L. Whitehead, Stephan L Zuchner, Lindsay A. Farrer, Eden R Martin, Gary W Beecham, Jonathan L. Haines, Jeffery M Vance, Michael Cuccaro, John Gilbert, Gerard D. Schellenberg, Regina M. Carney, Margaret A Pericak-Vance

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Objective: The genetic risk architecture of Alzheimer disease (AD) is complex with single pathogenic mutations leading to early-onset AD, while both rare and common genetic susceptibility variants contribute to the more widespread late-onset AD (LOAD); we sought to discover novel genes contributing to LOAD risk. Methods: Whole-exome sequencing and genome-wide genotyping were performed on 11 affected individuals in an extended family with an apparent autosomal dominant pattern of LOAD. Variants of interest were then evaluated in a large cohort of LOAD cases and aged controls. Results: We detected a single rare, nonsynonymous variant shared in all 11 LOAD individuals, a missense change in the tetratricopeptide repeat domain 3 (TTC3) gene. The missense variant, rs377155188 (p.S1038C), is predicted to be damaging. Affecteds-only multipoint linkage analysis demonstrated that this region of TTC3 has a LOD score of 2.66 in this family. Conclusion: The TTC3 p.S1038C substitution may represent a segregating, rare LOAD risk variant. Previous studies have shown that TTC3 expression is consistently reduced in LOAD patients and negatively correlated with AD neuropathology and that TTC3 is a regulator of Akt signaling, a key pathway disrupted in LOAD. This study demonstrates how utilizing whole-exome sequencing in a large, multigenerational family with a high incidence of LOAD could reveal a novel candidate gene.

Original languageEnglish (US)
Article numbere41
JournalNeurology: Genetics
Volume2
Issue number1
DOIs
StatePublished - Feb 1 2016

Fingerprint

Alzheimer Disease
Exome
Genes
Genetic Predisposition to Disease
Genome
Mutation
Incidence

ASJC Scopus subject areas

  • Clinical Neurology
  • Genetics(clinical)

Cite this

Segregation of a rare TTC3 variant in an extended family with late-onset Alzheimer disease. / Kohli, Martin A.; Cukier, Holly N; Hamilton-Nelson, Kara L.; Rolati, Sophie; Kunkle, Brian W.; Whitehead, Patrice L.; Zuchner, Stephan L; Farrer, Lindsay A.; Martin, Eden R; Beecham, Gary W; Haines, Jonathan L.; Vance, Jeffery M; Cuccaro, Michael; Gilbert, John; Schellenberg, Gerard D.; Carney, Regina M.; Pericak-Vance, Margaret A.

In: Neurology: Genetics, Vol. 2, No. 1, e41, 01.02.2016.

Research output: Contribution to journalArticle

Kohli, MA, Cukier, HN, Hamilton-Nelson, KL, Rolati, S, Kunkle, BW, Whitehead, PL, Zuchner, SL, Farrer, LA, Martin, ER, Beecham, GW, Haines, JL, Vance, JM, Cuccaro, M, Gilbert, J, Schellenberg, GD, Carney, RM & Pericak-Vance, MA 2016, 'Segregation of a rare TTC3 variant in an extended family with late-onset Alzheimer disease', Neurology: Genetics, vol. 2, no. 1, e41. https://doi.org/10.1212/NXG.0000000000000041
Kohli, Martin A. ; Cukier, Holly N ; Hamilton-Nelson, Kara L. ; Rolati, Sophie ; Kunkle, Brian W. ; Whitehead, Patrice L. ; Zuchner, Stephan L ; Farrer, Lindsay A. ; Martin, Eden R ; Beecham, Gary W ; Haines, Jonathan L. ; Vance, Jeffery M ; Cuccaro, Michael ; Gilbert, John ; Schellenberg, Gerard D. ; Carney, Regina M. ; Pericak-Vance, Margaret A. / Segregation of a rare TTC3 variant in an extended family with late-onset Alzheimer disease. In: Neurology: Genetics. 2016 ; Vol. 2, No. 1.
@article{5fc7ecbc89a747e38fb6c8e13f505e8e,
title = "Segregation of a rare TTC3 variant in an extended family with late-onset Alzheimer disease",
abstract = "Objective: The genetic risk architecture of Alzheimer disease (AD) is complex with single pathogenic mutations leading to early-onset AD, while both rare and common genetic susceptibility variants contribute to the more widespread late-onset AD (LOAD); we sought to discover novel genes contributing to LOAD risk. Methods: Whole-exome sequencing and genome-wide genotyping were performed on 11 affected individuals in an extended family with an apparent autosomal dominant pattern of LOAD. Variants of interest were then evaluated in a large cohort of LOAD cases and aged controls. Results: We detected a single rare, nonsynonymous variant shared in all 11 LOAD individuals, a missense change in the tetratricopeptide repeat domain 3 (TTC3) gene. The missense variant, rs377155188 (p.S1038C), is predicted to be damaging. Affecteds-only multipoint linkage analysis demonstrated that this region of TTC3 has a LOD score of 2.66 in this family. Conclusion: The TTC3 p.S1038C substitution may represent a segregating, rare LOAD risk variant. Previous studies have shown that TTC3 expression is consistently reduced in LOAD patients and negatively correlated with AD neuropathology and that TTC3 is a regulator of Akt signaling, a key pathway disrupted in LOAD. This study demonstrates how utilizing whole-exome sequencing in a large, multigenerational family with a high incidence of LOAD could reveal a novel candidate gene.",
author = "Kohli, {Martin A.} and Cukier, {Holly N} and Hamilton-Nelson, {Kara L.} and Sophie Rolati and Kunkle, {Brian W.} and Whitehead, {Patrice L.} and Zuchner, {Stephan L} and Farrer, {Lindsay A.} and Martin, {Eden R} and Beecham, {Gary W} and Haines, {Jonathan L.} and Vance, {Jeffery M} and Michael Cuccaro and John Gilbert and Schellenberg, {Gerard D.} and Carney, {Regina M.} and Pericak-Vance, {Margaret A}",
year = "2016",
month = "2",
day = "1",
doi = "10.1212/NXG.0000000000000041",
language = "English (US)",
volume = "2",
journal = "Neurology: Genetics",
issn = "2376-7839",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - Segregation of a rare TTC3 variant in an extended family with late-onset Alzheimer disease

AU - Kohli, Martin A.

AU - Cukier, Holly N

AU - Hamilton-Nelson, Kara L.

AU - Rolati, Sophie

AU - Kunkle, Brian W.

AU - Whitehead, Patrice L.

AU - Zuchner, Stephan L

AU - Farrer, Lindsay A.

AU - Martin, Eden R

AU - Beecham, Gary W

AU - Haines, Jonathan L.

AU - Vance, Jeffery M

AU - Cuccaro, Michael

AU - Gilbert, John

AU - Schellenberg, Gerard D.

AU - Carney, Regina M.

AU - Pericak-Vance, Margaret A

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Objective: The genetic risk architecture of Alzheimer disease (AD) is complex with single pathogenic mutations leading to early-onset AD, while both rare and common genetic susceptibility variants contribute to the more widespread late-onset AD (LOAD); we sought to discover novel genes contributing to LOAD risk. Methods: Whole-exome sequencing and genome-wide genotyping were performed on 11 affected individuals in an extended family with an apparent autosomal dominant pattern of LOAD. Variants of interest were then evaluated in a large cohort of LOAD cases and aged controls. Results: We detected a single rare, nonsynonymous variant shared in all 11 LOAD individuals, a missense change in the tetratricopeptide repeat domain 3 (TTC3) gene. The missense variant, rs377155188 (p.S1038C), is predicted to be damaging. Affecteds-only multipoint linkage analysis demonstrated that this region of TTC3 has a LOD score of 2.66 in this family. Conclusion: The TTC3 p.S1038C substitution may represent a segregating, rare LOAD risk variant. Previous studies have shown that TTC3 expression is consistently reduced in LOAD patients and negatively correlated with AD neuropathology and that TTC3 is a regulator of Akt signaling, a key pathway disrupted in LOAD. This study demonstrates how utilizing whole-exome sequencing in a large, multigenerational family with a high incidence of LOAD could reveal a novel candidate gene.

AB - Objective: The genetic risk architecture of Alzheimer disease (AD) is complex with single pathogenic mutations leading to early-onset AD, while both rare and common genetic susceptibility variants contribute to the more widespread late-onset AD (LOAD); we sought to discover novel genes contributing to LOAD risk. Methods: Whole-exome sequencing and genome-wide genotyping were performed on 11 affected individuals in an extended family with an apparent autosomal dominant pattern of LOAD. Variants of interest were then evaluated in a large cohort of LOAD cases and aged controls. Results: We detected a single rare, nonsynonymous variant shared in all 11 LOAD individuals, a missense change in the tetratricopeptide repeat domain 3 (TTC3) gene. The missense variant, rs377155188 (p.S1038C), is predicted to be damaging. Affecteds-only multipoint linkage analysis demonstrated that this region of TTC3 has a LOD score of 2.66 in this family. Conclusion: The TTC3 p.S1038C substitution may represent a segregating, rare LOAD risk variant. Previous studies have shown that TTC3 expression is consistently reduced in LOAD patients and negatively correlated with AD neuropathology and that TTC3 is a regulator of Akt signaling, a key pathway disrupted in LOAD. This study demonstrates how utilizing whole-exome sequencing in a large, multigenerational family with a high incidence of LOAD could reveal a novel candidate gene.

UR - http://www.scopus.com/inward/record.url?scp=84994521669&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84994521669&partnerID=8YFLogxK

U2 - 10.1212/NXG.0000000000000041

DO - 10.1212/NXG.0000000000000041

M3 - Article

AN - SCOPUS:84994521669

VL - 2

JO - Neurology: Genetics

JF - Neurology: Genetics

SN - 2376-7839

IS - 1

M1 - e41

ER -