{"doi":"10.1016/j.jalz.2017.07.096","title":"[O1–11–03]: CEREBROSPINAL FLUID ENDOPHENOTYPES PROVIDE INSIGHT INTO BIOLOGY UNDERLYING ALZHEIMER'S DISEASE","abstract":"Genome-wide association studies (GWAS) of disease endophenotypes provide power to identify novel variants and biological information important in disease pathology. Cerebrospinal fluid (CSF) levels of ptau181 and Aβ42, well established AD endophenotypes, allowed us to identify novel loci implicated in AD in a previous GWAS (n=1,296). Potential AD endophenotypes may also help identify novel variants associated with other disease phenotypes. TREM2 has been strongly associated with AD risk, and CSF levels of soluble TREM2 (sTREM2) are a promising AD biomarker. As we previously reported, TREM2 risk variants have highly complex effects on sTREM2 levels. CSF ptau181 and Aβ42 levels were collected from 3,189 unrelated individuals and linear regression was used to determine single nucleotide polymorphisms (SNPs) associated with these CSF proteins. We analyzed independent data sets to determine if associated SNPs were also associated with AD risk, AAO, or disease progression. Bioinformatics analyses were used to determine whether associated loci influenced gene expression. Our previously identified loci (3q28 near GMNC; 9p24.2 within GLIS3) and two novel loci (13q21.1 near PCDH8; 18q23 near NFATC1) were associated with ptau181. Novel variants associated with Aβ42 near GLIS1 (1p32.3) and within SERPINB1 (6p25) were also associated with risk and other AD phenotypes. Bioinformatics analyses revealed the significant variant for Aβ42 also influenced SERPINB1 expression in macrophages and whole blood, and may influence expression in human hippocampus. With a much larger GWAS we identified novel loci associated with CSF levels of ptau181 and with Aβ42 levels. Previous research in AD mouse models reported neutrophil migration across the blood brain barrier toward amyloid plaques. SERPINB1 is a key regulator of neutrophils and our results show it likely influences CSF Aβ42 (representative of plaque load). Our findings suggest adaptive immune response mechanisms and Aβ-associated pathology may be related. We are performing additional analyses to further explore potential impact of these findings in AD. Rare variant, gene-based, and pathway analyses will be used to further explore the role of immune response mechanisms in AD. We will also perform multiple phenotype analyses with CSF sTREM2, tau, ptau181, and Aβ42 to determine potential interactions.","journal":"Alzheimer's & Dementia","year":2017,"id":2235,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0739,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2017-07-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":27578,"name":"Manav Kapoor","orcid":"0000-0001-6682-940X","position":1,"is_corresponding":false},{"id":27579,"name":"Zeran Li","orcid":"0000-0002-7434-6499","position":2,"is_corresponding":false},{"id":27580,"name":"Oscar Harari","orcid":"0000-0002-2635-6975","position":3,"is_corresponding":false},{"id":27581,"name":"Kathleen Black","orcid":null,"position":4,"is_corresponding":false},{"id":27582,"name":"Jorge L. 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