Repeat length variations in ATXN1 and AR modify disease expression in Alzheimer's disease

Sarah L. Gardiner, Aster V.E. Harder, Yvonne J.M. Campman, Stella Trompet, Jacobijn Gussekloo, Martine J. van Belzen, Merel W. Boogaard, Raymund A.C. Roos, Iris E. Jansen, Yolande A.L. Pijnenburg, Philip Scheltens, Wiesje M. van der Flier, N. Ahmad Aziz

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Genomewide association studies (GWASs) have contributed greatly to unraveling the genetic basis of Alzheimer's disease (AD). However, a large amount of “missing heritability” remains. In this exploratory study, we investigated the effect of cytosine-adenine-guanine (CAG) repeats in polyglutamine disease–associated genes (PDAGs) on the risk of AD and its expression. In a cohort of 959 patients diagnosed with AD (Amsterdam Dementia cohort) and 4106 cognitively healthy participants (Leiden 85-plus Study and the Prospective Study of Pravastatin in the Elderly at Risk), we determined the CAG repeat sequences in ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1, and AR. We did not find a significant association between the risk of AD and variations in CAG repeat numbers of PDAGs. However, we found that differences in CAG repeat numbers in ATXN1, ATXN2, and AR were significantly associated with several clinical and imaging features in AD patients. Specifically, the association between memory performance in patients with AD and the CAG repeat size in the longer ATXN1 allele, and the association between atrophy in the medial temporal lobes and the CAG repeat number in the longer AR allele remained significant after correction for multiple testing. Our findings suggest that repeat polymorphisms in ATXN1 and AR can act as important genetic modifiers of AD, warranting further scrutiny of their role in its missing heritability and pathogenesis.

Original languageEnglish
Pages (from-to)230.e9-230.e17
JournalNeurobiology of Aging
Volume73
DOIs
Publication statusPublished - 1 Jan 2019

Cite this

Gardiner, S. L., Harder, A. V. E., Campman, Y. J. M., Trompet, S., Gussekloo, J., van Belzen, M. J., ... Aziz, N. A. (2019). Repeat length variations in ATXN1 and AR modify disease expression in Alzheimer's disease. Neurobiology of Aging, 73, 230.e9-230.e17. https://doi.org/10.1016/j.neurobiolaging.2018.09.007
Gardiner, Sarah L. ; Harder, Aster V.E. ; Campman, Yvonne J.M. ; Trompet, Stella ; Gussekloo, Jacobijn ; van Belzen, Martine J. ; Boogaard, Merel W. ; Roos, Raymund A.C. ; Jansen, Iris E. ; Pijnenburg, Yolande A.L. ; Scheltens, Philip ; van der Flier, Wiesje M. ; Aziz, N. Ahmad. / Repeat length variations in ATXN1 and AR modify disease expression in Alzheimer's disease. In: Neurobiology of Aging. 2019 ; Vol. 73. pp. 230.e9-230.e17.
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title = "Repeat length variations in ATXN1 and AR modify disease expression in Alzheimer's disease",
abstract = "Genomewide association studies (GWASs) have contributed greatly to unraveling the genetic basis of Alzheimer's disease (AD). However, a large amount of “missing heritability” remains. In this exploratory study, we investigated the effect of cytosine-adenine-guanine (CAG) repeats in polyglutamine disease–associated genes (PDAGs) on the risk of AD and its expression. In a cohort of 959 patients diagnosed with AD (Amsterdam Dementia cohort) and 4106 cognitively healthy participants (Leiden 85-plus Study and the Prospective Study of Pravastatin in the Elderly at Risk), we determined the CAG repeat sequences in ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1, and AR. We did not find a significant association between the risk of AD and variations in CAG repeat numbers of PDAGs. However, we found that differences in CAG repeat numbers in ATXN1, ATXN2, and AR were significantly associated with several clinical and imaging features in AD patients. Specifically, the association between memory performance in patients with AD and the CAG repeat size in the longer ATXN1 allele, and the association between atrophy in the medial temporal lobes and the CAG repeat number in the longer AR allele remained significant after correction for multiple testing. Our findings suggest that repeat polymorphisms in ATXN1 and AR can act as important genetic modifiers of AD, warranting further scrutiny of their role in its missing heritability and pathogenesis.",
keywords = "Alzheimer's disease, CAG repeat polymorphisms, Huntington disease, Missing heritability, Polyglutamine diseases",
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Gardiner, SL, Harder, AVE, Campman, YJM, Trompet, S, Gussekloo, J, van Belzen, MJ, Boogaard, MW, Roos, RAC, Jansen, IE, Pijnenburg, YAL, Scheltens, P, van der Flier, WM & Aziz, NA 2019, 'Repeat length variations in ATXN1 and AR modify disease expression in Alzheimer's disease' Neurobiology of Aging, vol. 73, pp. 230.e9-230.e17. https://doi.org/10.1016/j.neurobiolaging.2018.09.007

Repeat length variations in ATXN1 and AR modify disease expression in Alzheimer's disease. / Gardiner, Sarah L.; Harder, Aster V.E.; Campman, Yvonne J.M.; Trompet, Stella; Gussekloo, Jacobijn; van Belzen, Martine J.; Boogaard, Merel W.; Roos, Raymund A.C.; Jansen, Iris E.; Pijnenburg, Yolande A.L.; Scheltens, Philip; van der Flier, Wiesje M.; Aziz, N. Ahmad.

In: Neurobiology of Aging, Vol. 73, 01.01.2019, p. 230.e9-230.e17.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Repeat length variations in ATXN1 and AR modify disease expression in Alzheimer's disease

AU - Gardiner, Sarah L.

AU - Harder, Aster V.E.

AU - Campman, Yvonne J.M.

AU - Trompet, Stella

AU - Gussekloo, Jacobijn

AU - van Belzen, Martine J.

AU - Boogaard, Merel W.

AU - Roos, Raymund A.C.

AU - Jansen, Iris E.

AU - Pijnenburg, Yolande A.L.

AU - Scheltens, Philip

AU - van der Flier, Wiesje M.

AU - Aziz, N. Ahmad

PY - 2019/1/1

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N2 - Genomewide association studies (GWASs) have contributed greatly to unraveling the genetic basis of Alzheimer's disease (AD). However, a large amount of “missing heritability” remains. In this exploratory study, we investigated the effect of cytosine-adenine-guanine (CAG) repeats in polyglutamine disease–associated genes (PDAGs) on the risk of AD and its expression. In a cohort of 959 patients diagnosed with AD (Amsterdam Dementia cohort) and 4106 cognitively healthy participants (Leiden 85-plus Study and the Prospective Study of Pravastatin in the Elderly at Risk), we determined the CAG repeat sequences in ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1, and AR. We did not find a significant association between the risk of AD and variations in CAG repeat numbers of PDAGs. However, we found that differences in CAG repeat numbers in ATXN1, ATXN2, and AR were significantly associated with several clinical and imaging features in AD patients. Specifically, the association between memory performance in patients with AD and the CAG repeat size in the longer ATXN1 allele, and the association between atrophy in the medial temporal lobes and the CAG repeat number in the longer AR allele remained significant after correction for multiple testing. Our findings suggest that repeat polymorphisms in ATXN1 and AR can act as important genetic modifiers of AD, warranting further scrutiny of their role in its missing heritability and pathogenesis.

AB - Genomewide association studies (GWASs) have contributed greatly to unraveling the genetic basis of Alzheimer's disease (AD). However, a large amount of “missing heritability” remains. In this exploratory study, we investigated the effect of cytosine-adenine-guanine (CAG) repeats in polyglutamine disease–associated genes (PDAGs) on the risk of AD and its expression. In a cohort of 959 patients diagnosed with AD (Amsterdam Dementia cohort) and 4106 cognitively healthy participants (Leiden 85-plus Study and the Prospective Study of Pravastatin in the Elderly at Risk), we determined the CAG repeat sequences in ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1, and AR. We did not find a significant association between the risk of AD and variations in CAG repeat numbers of PDAGs. However, we found that differences in CAG repeat numbers in ATXN1, ATXN2, and AR were significantly associated with several clinical and imaging features in AD patients. Specifically, the association between memory performance in patients with AD and the CAG repeat size in the longer ATXN1 allele, and the association between atrophy in the medial temporal lobes and the CAG repeat number in the longer AR allele remained significant after correction for multiple testing. Our findings suggest that repeat polymorphisms in ATXN1 and AR can act as important genetic modifiers of AD, warranting further scrutiny of their role in its missing heritability and pathogenesis.

KW - Alzheimer's disease

KW - CAG repeat polymorphisms

KW - Huntington disease

KW - Missing heritability

KW - Polyglutamine diseases

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JF - Neurobiology of Aging

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Gardiner SL, Harder AVE, Campman YJM, Trompet S, Gussekloo J, van Belzen MJ et al. Repeat length variations in ATXN1 and AR modify disease expression in Alzheimer's disease. Neurobiology of Aging. 2019 Jan 1;73:230.e9-230.e17. https://doi.org/10.1016/j.neurobiolaging.2018.09.007