{"doi":"10.1101/2025.01.06.631528","title":"Ramp sequence may explain synonymous variant association with Alzheimer’s disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha ( <i>PILRA</i> )","abstract":"Abstract BACKGROUND Synonymous variant NC_000007.14:g.100373690T&gt;C ( rs2405442:T&gt;C ) in the Paired Immunoglobulin-like Type 2 Receptor Alpha ( PILRA ) gene was previously associated with decreased risk for Alzheimer’s disease (AD) in genome-wide association studies, but its biological impact is largely unknown. OBJECTIVE We hypothesized that rs2405442:T&gt;C decreases mRNA and protein levels by destroying a ramp of slowly translated codons at the 5’ end of PILRA . METHODS We assessed rs2405442:T&gt;C predicted effects on PILRA through quantitative polymerase chain reactions (qPCR) and enzyme-linked immunosorbent assays (ELISA) using Chinese hamster ovary (CHO) cells. RESULTS Both mRNA ( P =1.9184 × 10 −13 ) and protein ( P =0.01296) levels significantly decreased in the mutant versus the wildtype in the direction that we predicted based on destroying a ramp sequence. CONCLUSIONS We show that rs2405442:T&gt;C alone directly impacts PILRA mRNA and protein expression, and ramp sequences may play a role in regulating AD-associated genes without modifying the protein product. Research in Context Systematic review: Genetic variants identified through genome-wide association studies often lack biological support for their association with Alzheimer’s disease. Although synonymous variant rs2405442:T&gt;C in PILRA was previously reported as protective against Alzheimer’s disease, its effects have generally been attributed to linkage with missense variant, rs1859788:A&gt;G . Interpretation: We show that rs2405442:T&gt;C alone decreases mRNA and protein levels by destroying a ramp of slowly translated codons at the beginning of PILRA . We also show that a ramp sequence is present in PILRA and likely regulates mRNA and protein levels, thus offering a plausible biological mechanism explaining rs2405442:T&gt;C association with Alzheimer’s disease independent of rs1859788:A&gt;G . Future directions: We provide the first protocol to evaluate how disease-associated variants impact ramp sequences, which could explain why some genetic variants are reported by genome-wide association studies. Future studies might examine if the ramp sequence could be therapeutically targeted to regulate PILRA expression without changing the protein product.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":557011,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9466,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":565643,"name":"J. Anthony Brandon","orcid":"0009-0009-4094-7278","position":1,"is_corresponding":false},{"id":1457159,"name":"Lauren M. McKinnon","orcid":null,"position":2,"is_corresponding":false},{"id":1425837,"name":"Hady W. Sabra","orcid":"0009-0000-8549-4713","position":3,"is_corresponding":false},{"id":1405674,"name":"Chloe C. Lucido","orcid":null,"position":4,"is_corresponding":false},{"id":415545,"name":"Josue D. Gonzalez Murcia","orcid":"0000-0003-2951-8316","position":5,"is_corresponding":false},{"id":1161909,"name":"Kayla A. Nations","orcid":null,"position":6,"is_corresponding":false},{"id":44662,"name":"Samuel H. Payne","orcid":"0000-0002-8351-1994","position":7,"is_corresponding":false},{"id":694121,"name":"Mark Ebbert","orcid":"0000-0001-9158-4440","position":8,"is_corresponding":false},{"id":1457160,"name":"John SK Kauwe","orcid":null,"position":9,"is_corresponding":false},{"id":416079,"name":"Perry G. Ridge","orcid":"0000-0001-6944-2753","position":10,"is_corresponding":false},{"id":415546,"name":"Justin Miller","orcid":"0000-0002-5309-1570","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":null,"created_at":"2026-07-19T02:55:13.130091Z","pmid":"39829933","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}