Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project

Elizabeth E. Blue; Joshua C. Bis; Michael O. Dorschner; Debby W. Tsuang; Sandra M. Barral; Gary Beecham; Jennifer E. Below; William S. Bush; Mariusz Butkiewicz; Carlos Cruchaga; Anita Destefano; Lindsay A. Farrer; Alison Goate; Jonathan Haines; Jim Jaworski; Gyungah Jun; Brian Kunkle; Amanda Kuzma; Jenny J. Lee; Kathryn L. Lunetta; Yiyi Ma; Eden Martin; Adam Naj; Alejandro Q. Nato; Patrick Navas; Hiep Nguyen; Christiane Reitz; Dolly Reyes; William Salerno; Gerard D. Schellenberg; Sudha Seshadri; Harkirat Sohi; Timothy A. Thornton; Otto Valadares; Cornelia Van Duijn; Badri N. Vardarajan; Li San Wang; Eric Boerwinkle; Josée Dupuis; Margaret A. Pericak-Vance; Richard Mayeux; Ellen M. Wijsman

doi:10.1159/000485503

Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project

Elizabeth E. Blue, Joshua C. Bis, Michael O. Dorschner, Debby W. Tsuang, Sandra M. Barral, Gary Beecham, Jennifer E. Below, William S. Bush, Mariusz Butkiewicz, Carlos Cruchaga, Anita Destefano, Lindsay A. Farrer, Alison Goate, Jonathan Haines, Jim Jaworski, Gyungah Jun, Brian Kunkle, Amanda Kuzma, Jenny J. Lee, Kathryn L. LunettaYiyi Ma, Eden Martin, Adam Naj, Alejandro Q. Nato, Patrick Navas, Hiep Nguyen, Christiane Reitz, Dolly Reyes, William Salerno, Gerard D. Schellenberg, Sudha Seshadri, Harkirat Sohi, Timothy A. Thornton, Otto Valadares, Cornelia Van Duijn, Badri N. Vardarajan, Li San Wang, Eric Boerwinkle, Josée Dupuis, Margaret A. Pericak-Vance, Richard Mayeux, Ellen M. Wijsman

Research output: Contribution to journal › Article

6 Scopus citations

Abstract

Background/Aims: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer's disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP. Methods: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as "pathogenic" in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations. Results/Conclusions: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.

Original language	English (US)
Pages (from-to)	1-17
Number of pages	17
Journal	Dementia and Geriatric Cognitive Disorders
Volume	45
Issue number	1-2
DOIs	https://doi.org/10.1159/000485503
State	Published - May 1 2018
Externally published	Yes

Keywords

Alzheimer genetics
Alzheimer's disease
Arylsulfatase A pseudodeficiency
Candidate genes
ClinVar
Frontotemporal dementia
Pathogenicity
Rare variants

ASJC Scopus subject areas

Geriatrics and Gerontology
Cognitive Neuroscience
Psychiatry and Mental health

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Blue, E. E., Bis, J. C., Dorschner, M. O., Tsuang, D. W., Barral, S. M., Beecham, G., Below, J. E., Bush, W. S., Butkiewicz, M., Cruchaga, C., Destefano, A., Farrer, L. A., Goate, A., Haines, J., Jaworski, J., Jun, G., Kunkle, B., Kuzma, A., Lee, J. J., ... Wijsman, E. M. (2018). Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project. Dementia and Geriatric Cognitive Disorders, 45(1-2), 1-17. https://doi.org/10.1159/000485503

Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project. / Blue, Elizabeth E.; Bis, Joshua C.; Dorschner, Michael O.; Tsuang, Debby W.; Barral, Sandra M.; Beecham, Gary; Below, Jennifer E.; Bush, William S.; Butkiewicz, Mariusz; Cruchaga, Carlos; Destefano, Anita; Farrer, Lindsay A.; Goate, Alison; Haines, Jonathan; Jaworski, Jim; Jun, Gyungah; Kunkle, Brian; Kuzma, Amanda; Lee, Jenny J.; Lunetta, Kathryn L.; Ma, Yiyi; Martin, Eden; Naj, Adam; Nato, Alejandro Q.; Navas, Patrick; Nguyen, Hiep; Reitz, Christiane; Reyes, Dolly; Salerno, William; Schellenberg, Gerard D.; Seshadri, Sudha; Sohi, Harkirat; Thornton, Timothy A.; Valadares, Otto; Van Duijn, Cornelia; Vardarajan, Badri N.; Wang, Li San; Boerwinkle, Eric; Dupuis, Josée; Pericak-Vance, Margaret A.; Mayeux, Richard; Wijsman, Ellen M.

In: Dementia and Geriatric Cognitive Disorders, Vol. 45, No. 1-2, 01.05.2018, p. 1-17.

Research output: Contribution to journal › Article

Blue, EE, Bis, JC, Dorschner, MO, Tsuang, DW, Barral, SM, Beecham, G, Below, JE, Bush, WS, Butkiewicz, M, Cruchaga, C, Destefano, A, Farrer, LA, Goate, A, Haines, J, Jaworski, J, Jun, G, Kunkle, B, Kuzma, A, Lee, JJ, Lunetta, KL, Ma, Y, Martin, E, Naj, A, Nato, AQ, Navas, P, Nguyen, H, Reitz, C, Reyes, D, Salerno, W, Schellenberg, GD, Seshadri, S, Sohi, H, Thornton, TA, Valadares, O, Van Duijn, C, Vardarajan, BN, Wang, LS, Boerwinkle, E, Dupuis, J, Pericak-Vance, MA, Mayeux, R & Wijsman, EM 2018, 'Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project', Dementia and Geriatric Cognitive Disorders, vol. 45, no. 1-2, pp. 1-17. https://doi.org/10.1159/000485503

Blue, Elizabeth E. ; Bis, Joshua C. ; Dorschner, Michael O. ; Tsuang, Debby W. ; Barral, Sandra M. ; Beecham, Gary ; Below, Jennifer E. ; Bush, William S. ; Butkiewicz, Mariusz ; Cruchaga, Carlos ; Destefano, Anita ; Farrer, Lindsay A. ; Goate, Alison ; Haines, Jonathan ; Jaworski, Jim ; Jun, Gyungah ; Kunkle, Brian ; Kuzma, Amanda ; Lee, Jenny J. ; Lunetta, Kathryn L. ; Ma, Yiyi ; Martin, Eden ; Naj, Adam ; Nato, Alejandro Q. ; Navas, Patrick ; Nguyen, Hiep ; Reitz, Christiane ; Reyes, Dolly ; Salerno, William ; Schellenberg, Gerard D. ; Seshadri, Sudha ; Sohi, Harkirat ; Thornton, Timothy A. ; Valadares, Otto ; Van Duijn, Cornelia ; Vardarajan, Badri N. ; Wang, Li San ; Boerwinkle, Eric ; Dupuis, Josée ; Pericak-Vance, Margaret A. ; Mayeux, Richard ; Wijsman, Ellen M. / Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project. In: Dementia and Geriatric Cognitive Disorders. 2018 ; Vol. 45, No. 1-2. pp. 1-17.

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abstract = "Background/Aims: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer's disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP. Methods: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as {"}pathogenic{"} in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations. Results/Conclusions: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.",

keywords = "Alzheimer genetics, Alzheimer's disease, Arylsulfatase A pseudodeficiency, Candidate genes, ClinVar, Frontotemporal dementia, Pathogenicity, Rare variants",

author = "Blue, {Elizabeth E.} and Bis, {Joshua C.} and Dorschner, {Michael O.} and Tsuang, {Debby W.} and Barral, {Sandra M.} and Gary Beecham and Below, {Jennifer E.} and Bush, {William S.} and Mariusz Butkiewicz and Carlos Cruchaga and Anita Destefano and Farrer, {Lindsay A.} and Alison Goate and Jonathan Haines and Jim Jaworski and Gyungah Jun and Brian Kunkle and Amanda Kuzma and Lee, {Jenny J.} and Lunetta, {Kathryn L.} and Yiyi Ma and Eden Martin and Adam Naj and Nato, {Alejandro Q.} and Patrick Navas and Hiep Nguyen and Christiane Reitz and Dolly Reyes and William Salerno and Schellenberg, {Gerard D.} and Sudha Seshadri and Harkirat Sohi and Thornton, {Timothy A.} and Otto Valadares and {Van Duijn}, Cornelia and Vardarajan, {Badri N.} and Wang, {Li San} and Eric Boerwinkle and Jos{\'e}e Dupuis and Pericak-Vance, {Margaret A.} and Richard Mayeux and Wijsman, {Ellen M.}",

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T1 - Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project

AU - Blue, Elizabeth E.

AU - Bis, Joshua C.

AU - Dorschner, Michael O.

AU - Tsuang, Debby W.

AU - Barral, Sandra M.

AU - Beecham, Gary

AU - Below, Jennifer E.

AU - Bush, William S.

AU - Butkiewicz, Mariusz

AU - Cruchaga, Carlos

AU - Destefano, Anita

AU - Farrer, Lindsay A.

AU - Goate, Alison

AU - Haines, Jonathan

AU - Jaworski, Jim

AU - Jun, Gyungah

AU - Kunkle, Brian

AU - Kuzma, Amanda

AU - Lee, Jenny J.

AU - Lunetta, Kathryn L.

AU - Ma, Yiyi

AU - Martin, Eden

AU - Naj, Adam

AU - Nato, Alejandro Q.

AU - Navas, Patrick

AU - Nguyen, Hiep

AU - Reitz, Christiane

AU - Reyes, Dolly

AU - Salerno, William

AU - Schellenberg, Gerard D.

AU - Seshadri, Sudha

AU - Sohi, Harkirat

AU - Thornton, Timothy A.

AU - Valadares, Otto

AU - Van Duijn, Cornelia

AU - Vardarajan, Badri N.

AU - Wang, Li San

AU - Boerwinkle, Eric

AU - Dupuis, Josée

AU - Pericak-Vance, Margaret A.

AU - Mayeux, Richard

AU - Wijsman, Ellen M.

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Y1 - 2018/5/1

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AB - Background/Aims: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer's disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP. Methods: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as "pathogenic" in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations. Results/Conclusions: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.

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KW - Alzheimer's disease

KW - Arylsulfatase A pseudodeficiency

KW - Candidate genes

KW - ClinVar

KW - Frontotemporal dementia

KW - Pathogenicity

KW - Rare variants

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