News : 2016 : May

Study identifies deletion that may contribute to Alzheimer’s disease in African Americans

Researchers from the University of Miami Miller School of Medicine’s John P. Hussman Institute for Human Genomics (HIHG) have identified a deletion that may contribute to Alzheimer’s disease (AD) in African Americans in a study published in Neurology: Genetics (Cukier, et al, 2016). AD, the leading cause of dementia in the elderly, occurs at a higher frequency in diverse populations, with estimates of AD being twice as frequent in African Americans compared to non-Hispanic white populations. While differing ethnicities can share AD risk genes and alleles, the consequences may be different in distinct populations. Therefore, this study used targeted massively parallel sequencing of the ATP-binding cassette sub-family A member 7 (ABCA7) gene in African Americans with AD to identify potentially population specific risk variants. A 44 base pair deletion was detected; this error is predicted to remove almost three-fourths of the protein product.

Association testing of this deletion in two large African American datasets (discovery n=1,068; replication n=1,749) demonstrated an association of the variant with disease. While the deletion was prevalent in aged control individuals (9.7%), it was enriched in patients with AD (15.2%). The deletion was also independently identified through whole exome sequencing of AD families from the Dominican Republic, which have a high level of African ancestry. Examination of >3,000 non-Hispanic white individuals demonstrated that the deletion was virtually absent in this population. The study suggests that this common ABCA7 deletion could represent an ethnic specific, pathogenic alteration in AD.

The study was possible through the HIHG’s collaboration with investigators from Columbia University, University of Pennsylvania, North Carolina A&T State University, Boston University and Case Western Reserve University, as well as their involvement with the Alzheimer ’s Disease Genetics Consortium (ADGC). Individuals for this study were ascertained over the course of 10 years.

“One of the goals of genomic studies in Alzheimer disease is to identify new targets for the development of new therapies. These studies emphasize the importance of including diverse populations in genetics research in an effort to develop treatment targets that will benefit all ethnic groups,” said Dr. Margaret Pericak-Vance, PhD, Director of the John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Foundation Professor of Human Genomics.

“The deletion identified in this study may be a significant contributor to Alzheimer’s disease risk conferred by ABCA7 in African Americans,” said Dr. Holly Cukier, PhD, lead author of the paper and a Research Assistant Professor in the Department of Neurology and the John P. Hussman Institute for Human Genomics. “Most ABCA7 risk variants reported in white populations thus far have been relatively rare; by comparison, the deletion detected in our study occurs fairly frequently in African American populations. Moreover, the deletion can be detected in Dominican individuals, whom have African ancestry. This demonstrates the necessity of utilizing diverse populations to identify all genetic factors contributing to disease.”

Other University of Miami investigators include: Brian Kunkle, PhD, Sophie Rolati, MS, Kara L. Hamilton-Nelson, MPH, Martin A. Kohli, PhD, Patrice L. Whitehead, BS, Derek Van Booven, BS, Derek Dykxhoorn, PhD, Michael Cuccaro, PhD, Regina Carney, MD, Jeffery Vance, MD, PhD, John R. Gilbert, PhD, Gary Beecham, PhD and Eden Martin, PhD.