Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case–control study

Steele, Natasha Z.R.; Carr, Jessie S.; Bonham, Luke W.; Geier, Ethan G.; Damotte, Vincent; Miller, Zachary A.; Desikan, Rahul S.; Boehme, Kevin L.; Mukherjee, Shubhabrata; Crane, Paul K.; Kauwe, John S. K.; Kramer, Joel H.; Miller, Bruce L.; Coppola, Giovanni; Hollenbach, Jill A.; Huang, Yadong; Yokoyama, Jennifer S.

doi:10.1371/journal.pmed.1002272

Cited by 72 publications

(67 citation statements)

References 78 publications

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“…These results suggest that mechanistically, PHS may, in part, be capturing influence from other AD pathological pathways beyond amyloid and tau, a reflection of the complexity underlying AD pathogenesis involving neuroinflammation and immune regulation [3, 26], neurovascular [30], mitogenic and oxidative stress signaling pathways [29]. Alternatively, our findings may reflect that risk factors for pathology are not equivalent to pathology.…”

Section: Discussionmentioning

confidence: 89%

Polygenic hazard score: an enrichment marker for Alzheimer’s associated amyloid and tau deposition

et al. 2017

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There is an urgent need for identifying nondemented individuals at the highest risk of progressing to Alzheimer’s disease (AD) dementia. Here, we evaluated whether a recently validated polygenic hazard score (PHS) can be integrated with known in vivo cerebrospinal fluid (CSF) or positron emission tomography (PET) biomarkers of amyloid, and CSF tau pathology to prospectively predict cognitive and clinical decline in 347 cognitive normal (CN; baseline age range = 59.7–90.1, 98.85% white) and 599 mild cognitively impaired (MCI; baseline age range = 54.4–91.4, 98.83% white) individuals from the Alzheimer’s Disease Neuroimaging Initiative 1, GO, and 2. We further investigated the association of PHS with post-mortem amyloid load and neurofibrillary tangles in the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 485, age at death range = 71.3–108.3). In CN and MCI individuals, we found that amyloid and total tau positivity systematically varies as a function of PHS. For individuals in greater than the 50th percentile PHS, the positive predictive value for amyloid approached 100%; for individuals in less than the 25th percentile PHS, the negative predictive value for total tau approached 85%. High PHS individuals with amyloid and tau pathology showed the steepest longitudinal cognitive and clinical decline, even among APOE ε4 noncarriers. Among the CN subgroup, we similarly found that PHS was strongly associated with amyloid positivity and the combination of PHS and biomarker status significantly predicted longitudinal clinical progression. In the ROSMAP cohort, higher PHS was associated with higher post-mortem amyloid load and neurofibrillary tangles, even in APOE ε4 noncarriers. Together, our results show that even after accounting for APOE ε4 effects, PHS may be useful in MCI and preclinical AD therapeutic trials to enrich for biomarker-positive individuals at highest risk for short-term clinical progression.

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Section: Discussionmentioning

confidence: 89%

Polygenic hazard score: an enrichment marker for Alzheimer’s associated amyloid and tau deposition

et al. 2017

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“…The molecules encoded by the major histocompatibility complex (MHC) regions regulate the innate and adaptive arms of human immune response through antigen presentation, inflammation regulation and the complement system and the impact of this region in various immune-mediated conditions, including neurological diseases, has long been recognized. [4][5][6][7][8][9] The human MHC gene family maps to chromosome 6. With a size of nearly 5 Mbp it encodes approximately 165 protein-coding genes, many of them immune-related, 10 and comprises approximately 0Á13% of the human genome.…”

Section: The Human Major Histocompatibility Complex Region and Neurolmentioning

confidence: 99%

“…Finally, an HLA imputation-based analysis of 5919 European-ancestry AD Caucasian patients and 5771 controls identified the extended haplotype A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 as being associated with AD risk (P = 9Á6 9 10 À4 , OR = 1Á21) 8 in individuals who are negative for APOE 4. 8 The authors also found an association of the class I haplotype A*03:01~B*07:02, with higher CSF amyloid levels and a dose-dependent association of the DR15 haplotype with greater rates of cognitive decline and baseline levels of chemokine CC-4.…”

Section: Hla and Parkinson's Diseasementioning

confidence: 99%

“…As HLA class I molecules function as the primary ligand for several KIRs, it is possible that the class I association signals perceived for various diseases is, in fact, related to KIR function. In various neurological diseases, such as MS, 29,30,63,186 myasthenia gravis, [126][127][128] schizophrenia, 107,108,114 Parkinson's disease, 77,89 Alzheimer's disease 8,94,100 and amyotrophic lateral sclerosis, 140,141,145,146 the alleles of HLA-A, -B and -C that are recognized to function as cognate ligands for their respective KIR genes have been linked with disease (Table 2). Here, it is important to note that the majority of the identified HLA class I association with various neurological diseases described used an imputation approach from data obtained through GWAS rather than direct assay.…”

Section: Hla and Amyotrophic Lateral Sclerosismentioning

confidence: 99%

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The immunogenetics of neurological disease

2017

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Summary Genes encoding antigen‐presenting molecules within the human major histocompatibility complex (MHC) account for the highest component of genetic risk for many neurological diseases, such as multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. Myriad genetic, immunological and environmental factors may contribute to an individual's susceptibility to neurological disease. Here, we review and discuss the decades long research on the influence of genetic variation at the MHC locus and the role of immunogenetic killer cell immunoglobulin‐like receptor (KIR) loci in neurological diseases, including multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. The findings of immunogenetic association studies are consistent with a polygenic model of inheritance in the heterogeneous and multifactorial nature of complex traits in various neurological diseases. Future investigation is highly recommended to evaluate both coding and non‐coding variation in immunogenetic loci using high‐throughput high‐resolution next‐generation sequencing technologies in diverse ethnic groups to fully appreciate their role in neurological diseases.

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“…In other studies, however, these same alleles/combinations thereof have been established in neurological disorders such as Alzheimer's disease and multiple sclerosis, Parkinson's disease, narcolepsy, and autism (Table 4). [85][86][87] In addition, an increased risk of several inflammatory diseases such as sarcoidosis, especially nonresolving, pediatric-onset inflammatory bowel diseases (both Crohn's disease and ulcerative colitis), adult ulcerative colitis, and systemic lupus erythematosus in European descent, African-American, and Hispanic populations have been associated with DRB1*15:01/15:03 -related haplotypes. 35,38,88,89 Schizophrenia is another chronic neurologic disorder that affects nearly 1% of the world's population.…”

Section: Hla and Disease Associationsmentioning

confidence: 99%

The complexity and diversity of major histocompatibility complex challenge disease association studies

Lokki

Paakkanen

2018

HLA

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The major histocompatibility complex (MHC; 6p21.3) contains the most polymorphic genes, the most gene dense parts, and the highest diversity of functional gene clusters of the human genome. The clusters form haplotypes, which differ in linkage disequilibrium and show large variations in strength and extent between populations. Haplotype cis‐ and trans‐expression quantitative trait loci have increased the knowledge of regulatory interactions between multiple MHC genes. The detailed haplotype data offer a reference for future studies in immune‐mediated diseases and may unravel disease associations in conditions traditionally considered not to be immunologic. This article aims to describe the structural and functional variations of the MHC genes and haplotypes and their role on selected immune‐mediated diseases. In immune‐/inflammation‐mediated complex diseases, hundreds of common variants influence the development of the disease trait, but the individual variants have small effects on the disease phenotypes as seen in genome‐wide association studies. The genetic influence may still be significant on the cellular or molecular level. Nonetheless, the HLA alone is not sufficient as a susceptible genetic background to deduce the disease. For a comprehensive insight of the disease mechanisms, both immunological and genome assays methods are required.

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Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case–control study

Cited by 72 publications

References 78 publications

Polygenic hazard score: an enrichment marker for Alzheimer’s associated amyloid and tau deposition

Polygenic hazard score: an enrichment marker for Alzheimer’s associated amyloid and tau deposition

The immunogenetics of neurological disease

The complexity and diversity of major histocompatibility complex challenge disease association studies

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