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 › peer-review

9 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 › peer-review

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.

@article{e25f52408b76451f955e7da8c570c05c,

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

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.}",

note = "Funding Information: The biological samples and associated phenotypic data used in primary data analyses were stored at the study investigators{\textquoteright} institutions, and at the NCRAD (U24AG021886) at Indiana University, funded by the NIA. The associated phenotypic data used in the primary and secondary data analyses were provided by the study investigators, the NIA-funded ADCs, and the National Alzheimer{\textquoteright}s Coordinating Center (NACC; U01AG016976) and National Institute on Aging Genetics of Alzheimer{\textquoteright}s Disease Data Storage Site (NIAGADS; U24AG041689) at the University of Pennsylvania, funded by the NIA, as well as at the dbGaP funded by the NIH. This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. Contributors to the genetic analysis data included study investigators on projects that were individually funded by the NIA and other NIH institutes, as well as by private US organizations or foreign governmental or nongovernmental organizations. Funding Information: The ascertainment and selection of controls was supported by grant 1I01BX000531 from the Department of Veterans Affairs and grants P30 AG008017, P30 AG028383, P30 AG010124, P30 AG010161, P50 NS053488, P50 AG005131, P50 NS062684, P50 AG005136, P50 AG005133, R01 NS048595, R01 NS065070, R01 AG010845, and U01 AG006781 from the National Institutes of Health (NIH). For the Hispanic data: data collection for this project was supported by the Genetic Studies of Alzheimer's Disease in Caribbean Hispanics (EFIGA) funded by the National Institute on Aging (NIA) and by the NIH (5R37AG015473 and RF1AG015473). We acknowledge the EFIGA study participants and the EFIGA research and support staff for their contributions to this study. The ADSP is composed of two AD genetics consortia and three National Human Genome Research Institute (NHGRI)-funded Large Scale Sequencing and Analysis Centers (LSACs). The two AD genetics consortia are the ADGC, funded by NIA U01 AG032984, and the CHARGE consortium, funded by NIA R01 AG033193, the National Heart, Lung, and Blood Institute (NHLBI), other NIH institutes, and other foreign governmental and nongovernmental organizations. The Discovery Phase analysis of the sequencing data is supported through UF1AG047133 (to Drs. Schellenberg, Farrer, Pericak-Vance, Mayeux, and Haines); U01AG049505 to Dr. Seshadri; U01AG049506 to Dr. Boerwinkle; U01AG049507 to Dr. Wijsman; and U01AG049508 to Dr. Goate. The Discovery Extension Phase analysis is supported through U01AG052411 to Dr. Goate and U01AG052410 to Dr. Pericak-Vance. Data generation and harmonization in the Follow-Up Phases is supported through U54AG052427 (to Drs. Schellenberg and Wang). The CHARGE cohorts, with funding provided through 5RC2HL102419 and HL105756, include the following: the Atherosclerosis Risk in Communities (ARIC) Study, which is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), the Austrian Stroke Prevention Study (ASPS), the Cardiovascular Health Study (CHS), the Erasmus Rucphen Family Study (ERF), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). CHS research was supported through contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086, as well as through grants U01HL080295 and U01HL130114 from the NHLBI, with an additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629, R01AG15928, and R01AG20098 from the NIA. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The biological samples and associated phenotypic data used in primary data analyses were stored at the study investigators' institutions, and at the NCRAD (U24AG021886) at Indiana University, funded by the NIA. The associated phenotypic data used in the primary and secondary data analyses were provided by the study investigators, the NIA-funded ADCs, and the National Alzheimer's Coordinating Center (NACC; U01AG016976) and National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS; U24AG041689) at the University of Pennsylvania, funded by the NIA, as well as at the dbGaP funded by the NIH. This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. Contributors to the genetic analysis data included study investigators on projects that were individually funded by the NIA and other NIH institutes, as well as by private US organizations or foreign governmental or non governmental organizations. Funding Information: The ascertainment and selection ofcontrols was supported by grant 1I01BX000531 from the Department of Veterans Affairs and grants P30 AG008017, P30 AG028383, P30 AG010124, P30 AG010161, P50 NS053488, P50 AG005131, P50 NS062684, P50 AG005136, P50 AG005133, R01 NS048595, R01 NS065070, R01 AG010845, and U01 AG006781 from the National Institutes of Health (NIH). Funding Information: For the Hispanic data: data collection for this project was supported by the Genetic Studies of Alzheimer{\textquoteright}s Disease in Caribbean Hispanics (EFIGA) funded by the National Institute on Aging (NIA) and by the NIH (5R37AG015473 and RF1AG015473). We acknowledge the EFIGA study participants and the EFIGA research and support staff for their contributions to this study. Funding Information: The ADSP is composed of two AD genetics consortia and three National Human Genome Research Institute (NHGRI)-funded Large Scale Sequencing and Analysis Centers (LSACs). The two AD genetics consortia are the ADGC, funded by NIA U01 AG032984, and the CHARGE consortium, funded by NIA R01 AG033193, the National Heart, Lung, and Blood Institute (NHLBI), other NIH institutes, and other foreign governmental and nongovernmental organizations. The Discovery Phase analysis of the sequencing data is supported through UF1AG047133 (to Drs. Schellenberg, Farrer, Pericak-Vance, Mayeux, and Haines); U01AG049505 to Dr. Seshadri; U01AG049506 to Dr. Boerwinkle; U01AG049507 to Dr. Wijsman; and U01AG049508 to Dr. Goate. The Discovery Extension Phase analysis is supported through U01AG052411 to Dr. Goate and U01AG052410 to Dr. Pericak-Vance. Data generation and harmonization in the Follow-Up Phases is supported through U54AG052427 (to Drs. Schellenberg and Wang). Funding Information: The CHARGE cohorts, with funding provided through 5RC2HL102419 and HL105756, include the following: the Atherosclerosis Risk in Communities (ARIC) Study, which is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), the Austrian Stroke Prevention Study (ASPS), the Cardiovascular Health Study (CHS), the Erasmus Rucphen Family Study (ERF), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). CHS research was supported through contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086, as well as through grants U01HL080295 and U01HL130114 from the NHLBI, with an additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629, R01AG15928, and R01AG20098 from the NIA. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.",

year = "2018",

month = may,

day = "1",

doi = "10.1159/000485503",

language = "English (US)",

volume = "45",

pages = "1--17",

journal = "Dementia and Geriatric Cognitive Disorders",

issn = "1420-8008",

publisher = "S. Karger AG",

number = "1-2",

}

TY - JOUR

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.

N1 - Funding Information: The biological samples and associated phenotypic data used in primary data analyses were stored at the study investigators’ institutions, and at the NCRAD (U24AG021886) at Indiana University, funded by the NIA. The associated phenotypic data used in the primary and secondary data analyses were provided by the study investigators, the NIA-funded ADCs, and the National Alzheimer’s Coordinating Center (NACC; U01AG016976) and National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS; U24AG041689) at the University of Pennsylvania, funded by the NIA, as well as at the dbGaP funded by the NIH. This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. Contributors to the genetic analysis data included study investigators on projects that were individually funded by the NIA and other NIH institutes, as well as by private US organizations or foreign governmental or nongovernmental organizations. Funding Information: The ascertainment and selection of controls was supported by grant 1I01BX000531 from the Department of Veterans Affairs and grants P30 AG008017, P30 AG028383, P30 AG010124, P30 AG010161, P50 NS053488, P50 AG005131, P50 NS062684, P50 AG005136, P50 AG005133, R01 NS048595, R01 NS065070, R01 AG010845, and U01 AG006781 from the National Institutes of Health (NIH). For the Hispanic data: data collection for this project was supported by the Genetic Studies of Alzheimer's Disease in Caribbean Hispanics (EFIGA) funded by the National Institute on Aging (NIA) and by the NIH (5R37AG015473 and RF1AG015473). We acknowledge the EFIGA study participants and the EFIGA research and support staff for their contributions to this study. The ADSP is composed of two AD genetics consortia and three National Human Genome Research Institute (NHGRI)-funded Large Scale Sequencing and Analysis Centers (LSACs). The two AD genetics consortia are the ADGC, funded by NIA U01 AG032984, and the CHARGE consortium, funded by NIA R01 AG033193, the National Heart, Lung, and Blood Institute (NHLBI), other NIH institutes, and other foreign governmental and nongovernmental organizations. The Discovery Phase analysis of the sequencing data is supported through UF1AG047133 (to Drs. Schellenberg, Farrer, Pericak-Vance, Mayeux, and Haines); U01AG049505 to Dr. Seshadri; U01AG049506 to Dr. Boerwinkle; U01AG049507 to Dr. Wijsman; and U01AG049508 to Dr. Goate. The Discovery Extension Phase analysis is supported through U01AG052411 to Dr. Goate and U01AG052410 to Dr. Pericak-Vance. Data generation and harmonization in the Follow-Up Phases is supported through U54AG052427 (to Drs. Schellenberg and Wang). The CHARGE cohorts, with funding provided through 5RC2HL102419 and HL105756, include the following: the Atherosclerosis Risk in Communities (ARIC) Study, which is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), the Austrian Stroke Prevention Study (ASPS), the Cardiovascular Health Study (CHS), the Erasmus Rucphen Family Study (ERF), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). CHS research was supported through contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086, as well as through grants U01HL080295 and U01HL130114 from the NHLBI, with an additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629, R01AG15928, and R01AG20098 from the NIA. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The biological samples and associated phenotypic data used in primary data analyses were stored at the study investigators' institutions, and at the NCRAD (U24AG021886) at Indiana University, funded by the NIA. The associated phenotypic data used in the primary and secondary data analyses were provided by the study investigators, the NIA-funded ADCs, and the National Alzheimer's Coordinating Center (NACC; U01AG016976) and National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS; U24AG041689) at the University of Pennsylvania, funded by the NIA, as well as at the dbGaP funded by the NIH. This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. Contributors to the genetic analysis data included study investigators on projects that were individually funded by the NIA and other NIH institutes, as well as by private US organizations or foreign governmental or non governmental organizations. Funding Information: The ascertainment and selection ofcontrols was supported by grant 1I01BX000531 from the Department of Veterans Affairs and grants P30 AG008017, P30 AG028383, P30 AG010124, P30 AG010161, P50 NS053488, P50 AG005131, P50 NS062684, P50 AG005136, P50 AG005133, R01 NS048595, R01 NS065070, R01 AG010845, and U01 AG006781 from the National Institutes of Health (NIH). Funding Information: For the Hispanic data: data collection for this project was supported by the Genetic Studies of Alzheimer’s Disease in Caribbean Hispanics (EFIGA) funded by the National Institute on Aging (NIA) and by the NIH (5R37AG015473 and RF1AG015473). We acknowledge the EFIGA study participants and the EFIGA research and support staff for their contributions to this study. Funding Information: The ADSP is composed of two AD genetics consortia and three National Human Genome Research Institute (NHGRI)-funded Large Scale Sequencing and Analysis Centers (LSACs). The two AD genetics consortia are the ADGC, funded by NIA U01 AG032984, and the CHARGE consortium, funded by NIA R01 AG033193, the National Heart, Lung, and Blood Institute (NHLBI), other NIH institutes, and other foreign governmental and nongovernmental organizations. The Discovery Phase analysis of the sequencing data is supported through UF1AG047133 (to Drs. Schellenberg, Farrer, Pericak-Vance, Mayeux, and Haines); U01AG049505 to Dr. Seshadri; U01AG049506 to Dr. Boerwinkle; U01AG049507 to Dr. Wijsman; and U01AG049508 to Dr. Goate. The Discovery Extension Phase analysis is supported through U01AG052411 to Dr. Goate and U01AG052410 to Dr. Pericak-Vance. Data generation and harmonization in the Follow-Up Phases is supported through U54AG052427 (to Drs. Schellenberg and Wang). Funding Information: The CHARGE cohorts, with funding provided through 5RC2HL102419 and HL105756, include the following: the Atherosclerosis Risk in Communities (ARIC) Study, which is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), the Austrian Stroke Prevention Study (ASPS), the Cardiovascular Health Study (CHS), the Erasmus Rucphen Family Study (ERF), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). CHS research was supported through contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086, as well as through grants U01HL080295 and U01HL130114 from the NHLBI, with an additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629, R01AG15928, and R01AG20098 from the NIA. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

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.

KW - Alzheimer genetics

KW - Alzheimer's disease

KW - Arylsulfatase A pseudodeficiency

KW - Candidate genes

KW - ClinVar

KW - Frontotemporal dementia

KW - Pathogenicity

KW - Rare variants

UR - http://www.scopus.com/inward/record.url?scp=85042709194&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042709194&partnerID=8YFLogxK

U2 - 10.1159/000485503

DO - 10.1159/000485503

M3 - Article

C2 - 29486463

AN - SCOPUS:85042709194

VL - 45

SP - 1

EP - 17

JO - Dementia and Geriatric Cognitive Disorders

JF - Dementia and Geriatric Cognitive Disorders

SN - 1420-8008

IS - 1-2

ER -

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

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