Abstract An extended haplotype on chromosome 3 is the major genetic risk factor for severe COVID-19. The risk haplotype, which was inherited from Neanderthals, decreases the expression of several cytokine receptors, including CCR5. Recently, a study based on three general population cohorts indicated that the minor allele of one of the variants in the haplotype (rs17713054) protects against HIV infection. We thus expected this allele to be over-represented in highly exposed individuals who remain uninfected (exposed seronegative individuals, ESN). To perform a meta-analysis, we genotyped rs17713054 in three ESN cohorts of European ancestry exposed to HIV through different routes. No evidence of association was detected in the single cohorts. The meta-analysis also failed to detect any effect of the variant on protection from HIV-1. The same results were obtained in a Cox-regression analysis for the time to seroconversion. An in-vitro infection assay did not detect differences in viral replication as a function of rs17713054 genotype status. We conclude that the rs17713054 minor allele is not associated with the ESN phenotype and does not modulate HIV infection in vitro.
Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series. ; The authors would like to thank patients and controls who participated in this project. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Fundación bancaria "La Caixa", Grifols SA, Fundació ACE, and ISCIII (Ministry of Health, Spain). They also want to thank the private sponsors who support the basic and clinical projects of our institution (Piramal AG, Laboratorios Echevarne, Araclon Biotech S.A., and Fundació ACE). They are indebted to the Trinitat Port‐Carbó legacy and her family for their support of Fundació ACE research programs. Fundació ACE is a participating center in the Dementia Genetics Spanish Consortium (DEGESCO). A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, and PI17/01474. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)‐Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER‐ "Una manera de Hacer Europa"). L.M.R. is supported by Consejería de Salud de la Junta de Andalucía (grant PI‐0001/2017). Control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (www.bancoadn.org, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain); they were processed after standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. The present work was performed as part of the Biochemistry, Molecular Biology, and Biomedicine doctoral program of S. Moreno‐Grau at Universitat Autònoma de Barcelona (Barcelona, Spain). Data collection and sharing for this project was partially funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH‐12–2–0012). The ADNI is funded by the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering, as well as through generous contributions from the following: AbbVie; the Alzheimer's Association; the Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol‐Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann‐La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study was coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California. The AddNeuroMed data are from a public‐private partnership supported by EFPIA companies and SMEs as part of InnoMed (Innovative Medicines in Europe), an integrated project funded by the European Union of the Sixth Framework program priority FP6–2004‐LIFESCIHEALTH‐5. Clinical leads responsible for data collection are Iwona Kłoszewska (Lodz), Simon Lovestone (London), Patrizia Mecocci (Perugia), Hilkka Soininen (Kuopio), Magda Tsolaki (Thessaloniki), and Bruno Vellas (Toulouse). Imaging leads are Andy Simmons (London), Lars‐Olad Wahlund (Stockholm), and Christian Spenger (Zurich). Bioinformatics leads are Richard Dobson (London) and Stephen Newhouse (London). Funding support for the Alzheimer's Disease Genetics Consortium (ADGC) was provided through the NIA Division of Neuroscience (U01‐AG032984). The genotypic and associated phenotypic data used in the study "Multi‐Site Collaborative Study for Genotype‐Phenotype Associations in Alzheimer's Disease (GenADA)" were provided by GlaxoSmithKline, R&D Limited. The data sets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000219. The Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr. Nilüfer Ertekin‐Taner and Dr. Steven G. Younkin at the Mayo Clinic in Jacksonville, FL, used samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Data c ; Sí
