Linkage of Alzheimer disease families with Puerto Rican ancestry identifies a chromosome 9 locus

Farid Rajabli; Briseida E Feliciano-Astacio; Holly N Cukier; Liyong Wang; Anthony J Griswold; Kara L Hamilton-Nelson; Larry D Adams; Vanessa C Rodriguez; Pedro R Mena; Sergio Tejada; Katrina Celis; Patrice L Whitehead; Derek J Van Booven; Natalia K Hofmann; Parker L Bussies; Michael Prough; Angel Chinea; Nereida I Feliciano; Badri N Vardarajan; Christiane Reitz; Joseph H Lee; Martin J Prince; Ivonne Z Jimenez; Richard P Mayeux; Heriberto Acosta; Clifton L Dalgard; Jonathan L Haines; Jeffery M Vance; Michael L Cuccaro; Gary W Beecham; Margaret A Pericak-Vance

doi:10.1016/j.neurobiolaging.2021.02.019

Linkage of Alzheimer disease families with Puerto Rican ancestry identifies a chromosome 9 locus

Neurobiol Aging. 2021 Aug:104:115.e1-115.e7. doi: 10.1016/j.neurobiolaging.2021.02.019. Epub 2021 Feb 28.

Authors

Farid Rajabli¹, Briseida E Feliciano-Astacio², Holly N Cukier³, Liyong Wang⁴, Anthony J Griswold⁴, Kara L Hamilton-Nelson¹, Larry D Adams¹, Vanessa C Rodriguez¹, Pedro R Mena¹, Sergio Tejada¹, Katrina Celis¹, Patrice L Whitehead¹, Derek J Van Booven¹, Natalia K Hofmann¹, Parker L Bussies¹, Michael Prough¹, Angel Chinea², Nereida I Feliciano⁵, Badri N Vardarajan⁶, Christiane Reitz⁶, Joseph H Lee⁶, Martin J Prince⁷, Ivonne Z Jimenez⁸, Richard P Mayeux⁶, Heriberto Acosta⁹, Clifton L Dalgard¹⁰, Jonathan L Haines¹¹, Jeffery M Vance³, Michael L Cuccaro⁴, Gary W Beecham⁴, Margaret A Pericak-Vance¹²

Affiliations

¹ John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
² Universidad Central del Caribe, Bayamón, PR, USA.
³ John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA; Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
⁴ John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
⁵ Hospital De Psiquiatría Estatal Dr. Ramón Fernández Marina-Centro Médico, San Juan, PR, USA.
⁶ Departments of Neurology, Psychiatry, and Epidemiology, Gertrude H. Sergievsky Center, Taub Institute for Research on the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁷ Department of Epidemiological Psychiatry, Centre for Public Mental Health, Institute of Psychiatry, King's College, London, UK.
⁸ University of Puerto Rico School of Medicine, San Juan, PR, USA.
⁹ Clinica de la Memoria, San Juan, PR, USA.
¹⁰ Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
¹¹ Department of Population & Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
¹² John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA; Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address: [email protected].

PMID: 33902942
PMCID: PMC8851406
DOI: 10.1016/j.neurobiolaging.2021.02.019

Abstract

The genetic admixture of Caribbean Hispanics provides an opportunity to discover novel genetic factors in Alzheimer disease (AD). We sought to identify genetic variants for AD through a family-based design using the Puerto Rican (PR) Alzheimer Disease Initiative (PRADI). Whole-genome sequencing (WGS) and parametric linkage analysis were performed for 100 individuals from 23 multiplex PRADI families. Variants were prioritized by minor allele frequency (<0.01), functional potential [combined annotation dependent depletion score (CADD) >10], and co-segregation with AD. Variants were further ranked using an independent PR case-control WGS dataset (PR10/66). A genome-wide significant linkage peak was found in 9p21 with a heterogeneity logarithm of the odds score (HLOD) >5.1, which overlaps with an AD linkage region from two published independent studies. The region harbors C9orf72, but no expanded repeats were observed in the families. Seven variants prioritized by the PRADI families also displayed evidence for association in the PR10/66 (p < 0.05), including a missense variant in UNC13B. Our study demonstrated the importance of family-based design and WGS in genetic study of AD.

Keywords: Alzheimer disease; Chromosome 9; Genetic linkage; Puerto Ricans; Underserved populations.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / genetics*
C9orf72 Protein / genetics
Chromosomes, Human, Pair 9 / genetics*
Genetic Linkage*
Genetic Variation / genetics*
Genome-Wide Association Study*
Hispanic or Latino / genetics
Humans
Nerve Tissue Proteins / genetics
Whole Genome Sequencing

Substances

C9orf72 Protein
C9orf72 protein, human
Nerve Tissue Proteins
UNC13B protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding