title: Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case-control study.
abstract: BACKGROUND
  Alzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA) complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD. Contributing to this difficulty are the complex genetic organization of the HLA region, differences in sequencing and allelic imputation methods, and diversity across ethnic populations.
  
  
  RESULTS
  Building on prior work linking the HLA to AD, we used a robust imputation method on two separate case-control cohorts to examine the relationship between HLA haplotypes and AD risk in 309 individuals (191 AD, 118 cognitively normal [CN] controls) from the San Francisco-based University of California, San Francisco (UCSF) Memory and Aging Center (collected between 1999-2015) and 11,381 individuals (5,728 AD, 5,653 CN controls) from the Alzheimer's Disease Genetics Consortium (ADGC), a National Institute on Aging (NIA)-funded national data repository (reflecting samples collected between 1984-2012). We also examined cerebrospinal fluid (CSF) biomarker measures for patients seen between 2005-2007 and longitudinal cognitive data from the Alzheimer's Disease Neuroimaging Initiative (n = 346, mean follow-up 3.15 ± 2.04 y in AD individuals) to assess the clinical relevance of identified risk haplotypes. The strongest association with AD risk occurred with major histocompatibility complex (MHC) haplotype A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 (p = 9.6 x 10-4, odds ratio [OR] [95% confidence interval] = 1.21 [1.08-1.37]) in the combined UCSF + ADGC cohort. Secondary analysis suggested that this effect may be driven primarily by individuals who are negative for the established AD genetic risk factor, apolipoprotein E (APOE) ɛ4. Separate analyses of class I and II haplotypes further supported the role of class I haplotype A*03:01~B*07:02 (p = 0.03, OR = 1.11 [1.01-1.23]) and class II haplotype DRB1*15:01- DQA1*01:02- DQB1*06:02 (DR15) (p = 0.03, OR = 1.08 [1.01-1.15]) as risk factors for AD. We followed up these findings in the clinical dataset representing the spectrum of cognitively normal controls, individuals with mild cognitive impairment, and individuals with AD to assess their relevance to disease. Carrying A*03:01~B*07:02 was associated with higher CSF amyloid levels (p = 0.03, β ± standard error = 47.19 ± 21.78). We also found a dose-dependent association between the DR15 haplotype and greater rates of cognitive decline (greater impairment on the 11-item Alzheimer's Disease Assessment Scale cognitive subscale [ADAS11] over time [p = 0.03, β ± standard error = 0.7 ± 0.3]; worse forgetting score on the Rey Auditory Verbal Learning Test (RAVLT) over time [p = 0.02, β ± standard error = -0.2 ± 0.06]). In a subset of the same cohort, dose of DR15 was also associated with higher baseline levels of chemokine CC-4, a biomarker of inflammation (p = 0.005, β ± standard error = 0.08 ± 0.03). The main study limitations are that the results represent only individuals of European-ancestry and clinically diagnosed individuals, and that our study used imputed genotypes for a subset of HLA genes.
  
  
  CONCLUSIONS
  We provide evidence that variation in the HLA locus-including risk haplotype DR15-contributes to AD risk. DR15 has also been associated with multiple sclerosis, and its component alleles have been implicated in Parkinson disease and narcolepsy. Our findings thus raise the possibility that DR15-associated mechanisms may contribute to pan-neuronal disease vulnerability.
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America.|University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Natasha Z R
authors.initials: NZ
authors.lastname: Steele
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America.|Gladstone Institute of Neurological Disease, San Francisco, California, United States of America.
authors.forename: Jessie S
authors.identifier: http://orcid.org/0000-0001-6247-7494
authors.initials: JS
authors.lastname: Carr
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America.|Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Luke W
authors.initials: LW
authors.lastname: Bonham
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Ethan G
authors.initials: EG
authors.lastname: Geier
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Vincent
authors.initials: V
authors.lastname: Damotte
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Zachary A
authors.identifier: http://orcid.org/0000-0002-5991-3053
authors.initials: ZA
authors.lastname: Miller
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Rahul S
authors.identifier: http://orcid.org/0000-0002-4151-6017
authors.initials: RS
authors.lastname: Desikan
authors.affiliation: Brigham Young University, Provo, Utah, United States of America.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Boehme
authors.affiliation: University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Shubhabrata
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crane
authors.affiliation: Brigham Young University, Provo, Utah, United States of America.
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Joel H
authors.initials: JH
authors.lastname: Kramer
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Departments of Neurology and Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Giovanni
authors.identifier: http://orcid.org/0000-0003-2105-1061
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Hollenbach
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America.|Gladstone Institute of Neurological Disease, San Francisco, California, United States of America.|Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Jennifer S
authors.identifier: http://orcid.org/0000-0001-7274-2634
authors.initials: JS
authors.lastname: Yokoyama
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D005260:Female; D006680:HLA Antigens / Q000134:cerebrospinal fluid / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D012495:San Francisco / Q000453:epidemiology; D014481:United States / Q000453:epidemiology
chemical_list: D006680:HLA Antigens