. 2018 Mar 13;5(4):406-417.

doi: 10.1002/acn3.537. eCollection 2018 Apr.

Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer's disease

Badri N Vardarajan^{1

2

3}, Sandra Barral^{1

2

4}, James Jaworski⁵, Gary W Beecham⁵, Elizabeth Blue⁶, Giuseppe Tosto^{1

2}, Dolly Reyes-Dumeyer^{1

2}, Martin Medrano⁷, Rafael Lantigua^{1

8}, Adam Naj⁹, Timothy Thornton¹⁰, Anita DeStefano¹¹, Eden Martin⁵, Li-San Wang⁹, Lisa Brown¹⁰, William Bush¹², Cornelia van Duijn¹³, Allison Goate¹⁴, Lindsay Farrer¹¹, Jonathan L Haines¹², Eric Boerwinkle¹⁵, Gerard Schellenberg⁹, Ellen Wijsman^{6

10}, Margaret A Pericak-Vance⁵, Richard Mayeux^{1

2

3

16

17}; Alzheimer's Disease Sequencing Project; Li-San Wang^{1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17}

Collaborators, Affiliations

Collaborators

Alzheimer's Disease Sequencing Project:
Thomas H Mosley, Laura Cantwell, Micah Childress, Yi-Fan Chou, Rebecca Cweibel, Prabhakaran Gangadharan, Amanda Kuzma, Han-Jen Lin, John Malamon, Elisabeth Mlynarski, Adam Naj, Liming Qu, Gerard Schellenberg, Otto Valladares, Weixin Wang, Nancy Zhang, Jennifer E Below, Eric Boerwinkle, Jan Bressler, Myriam Fornage, Xueqiu Jian, Xiaoming Liu, Joshua C Bis, Elizabeth Blue, Lisa Brown, Tyler Day, Michael Dorschner, Rafael Nafikov, Pat Navas, Hiep Nguyen, Bruce Psaty, Kenneth Rice, Mohamad Saad, Harkirat Sohi, Timothy Thornton, Debby Tsuang, Bowen Wang, Ellen Wijsman, Elizabeth Appelbaum, Carlos Cruchaga, Daniel C Koboldt, Jason Waligorski

Affiliations

¹ The Taub Institute for Research on Alzheimer's Disease and the Aging Brain New York.
² The Gertrude H. Sergievsky Center Columbia University The New York Presbyterian Hospital New York New York.
³ Department of Systems Biology Columbia University The New York Presbyterian Hospital New York New York.
⁴ The Department of Neurology Columbia University The New York Presbyterian Hospital New York New York.
⁵ Dr. John T. Macdonald Foundation Department of Human Genetics The John P. Hussman Institute for Human Genomics Miami Florida.
⁶ Division of Medical Genetics Department of Medicine University of Washington Seattle Washington.
⁷ School of Medicine Mother and Teacher Pontifical Catholic University Santiago Dominican Republic.
⁸ Department of Medicine Columbia University The New York Presbyterian Hospital New York New York.
⁹ School of Medicine University of Pennsylvania Philadelphia Pennsylvania.
¹⁰ Department of Biostatistics University of Washington Seattle Washington.
¹¹ Boston University School of Medicine Boston Massachusetts.
¹² Department of Biostatistics and Epidemiology Case Western Reserve University Cleveland Ohio.
¹³ Erasmus University Medical Center Rotterdam Netherlands.
¹⁴ Mount Sinai School of Medicine New York New York.
¹⁵ University of Texas Houston Texas.
¹⁶ Department of Psychiatry Columbia University The New York Presbyterian Hospital New York New York.
¹⁷ The Department of Epidemiology School of Public Health Columbia University New York New York.

PMID: 29688227
PMCID: PMC5899906
DOI: 10.1002/acn3.537

Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer's disease

Badri N Vardarajan et al. Ann Clin Transl Neurol. 2018.

. 2018 Mar 13;5(4):406-417.

doi: 10.1002/acn3.537. eCollection 2018 Apr.

Authors

Collaborators

Alzheimer's Disease Sequencing Project:
Thomas H Mosley, Laura Cantwell, Micah Childress, Yi-Fan Chou, Rebecca Cweibel, Prabhakaran Gangadharan, Amanda Kuzma, Han-Jen Lin, John Malamon, Elisabeth Mlynarski, Adam Naj, Liming Qu, Gerard Schellenberg, Otto Valladares, Weixin Wang, Nancy Zhang, Jennifer E Below, Eric Boerwinkle, Jan Bressler, Myriam Fornage, Xueqiu Jian, Xiaoming Liu, Joshua C Bis, Elizabeth Blue, Lisa Brown, Tyler Day, Michael Dorschner, Rafael Nafikov, Pat Navas, Hiep Nguyen, Bruce Psaty, Kenneth Rice, Mohamad Saad, Harkirat Sohi, Timothy Thornton, Debby Tsuang, Bowen Wang, Ellen Wijsman, Elizabeth Appelbaum, Carlos Cruchaga, Daniel C Koboldt, Jason Waligorski

Affiliations

¹ The Taub Institute for Research on Alzheimer's Disease and the Aging Brain New York.
² The Gertrude H. Sergievsky Center Columbia University The New York Presbyterian Hospital New York New York.
³ Department of Systems Biology Columbia University The New York Presbyterian Hospital New York New York.
⁴ The Department of Neurology Columbia University The New York Presbyterian Hospital New York New York.
⁵ Dr. John T. Macdonald Foundation Department of Human Genetics The John P. Hussman Institute for Human Genomics Miami Florida.
⁶ Division of Medical Genetics Department of Medicine University of Washington Seattle Washington.
⁷ School of Medicine Mother and Teacher Pontifical Catholic University Santiago Dominican Republic.
⁸ Department of Medicine Columbia University The New York Presbyterian Hospital New York New York.
⁹ School of Medicine University of Pennsylvania Philadelphia Pennsylvania.
¹⁰ Department of Biostatistics University of Washington Seattle Washington.
¹¹ Boston University School of Medicine Boston Massachusetts.
¹² Department of Biostatistics and Epidemiology Case Western Reserve University Cleveland Ohio.
¹³ Erasmus University Medical Center Rotterdam Netherlands.
¹⁴ Mount Sinai School of Medicine New York New York.
¹⁵ University of Texas Houston Texas.
¹⁶ Department of Psychiatry Columbia University The New York Presbyterian Hospital New York New York.
¹⁷ The Department of Epidemiology School of Public Health Columbia University New York New York.

PMID: 29688227
PMCID: PMC5899906
DOI: 10.1002/acn3.537

Abstract

Objective: To identify rare causal variants underlying known loci that segregate with late-onset Alzheimer's disease (LOAD) in multiplex families.

Methods: We analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case-control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene-based associations with disease within LOAD GWAS loci.

Results: A variant in AKAP9, p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07-30.9, P = 0.041). In addition, missense mutations in MYRF and ASRGL1 under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow-up genotyping both were nominally significant (P < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including CR1 (P = 0.049), BIN1 (P = 0.0098) and SLC24A4 (P = 0.040).

Conclusions and relevance: Rare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.

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Figures

**Figure 1**
Filtering strategy to prioritize variants for follow‐up analyses in the validation sample.

**Figure 2**
Segregation pattern of *AKAP9* p.R434W in family 285 (Refer to Table S8 for conversion for EFIGA to ADSP ids).

**Figure 3**
Segregation pattern of *AKAP9* p.R434W in family 348 (Refer to Table S9 for conversion for EFIGA to ADSP ids).

See this image and copyright information in PMC

References

1. Harold D, Abraham R, Hollingworth P, et al. Genome‐wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet 2009;41:1088–1093. - PMC - PubMed
1. Hollingworth P, Harold D, Sims R, et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet 2011;43:429–435. - PMC - PubMed
1. Lambert JC, Heath S, Even G, et al. Genome‐wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 2009;41:1094–1099. - PubMed
1. Lambert JC, Ibrahim‐Verbaas CA, Harold D, et al. Meta‐analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 2013;45:1452–1458. - PMC - PubMed
1. Naj AC, Jun G, Beecham GW, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late‐onset Alzheimer's disease. Nat Genet 2011;43:436–441. - PMC - PubMed

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Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer's disease

Collaborators

Affiliations

Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer's disease

Authors

Collaborators

Affiliations

Abstract

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Miscellaneous