Ramp sequence may explain synonymous variant association with Alzheimer's disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA)

Miller, J. B.; Brandon, J. A.; McKinnon, L. M.; Sabra, H. W.; Lucido, C. C.; Murcia, J. D. G.; Nations, K. A.; Payne, S. H.; Ebbert, M.; Kauwe, J. S.; Ridge, P. G.

doi:10.1101/2025.01.06.631528

bioRxiv · 10.1101/2025.01.06.631528

Ramp sequence may explain synonymous variant association with Alzheimer's disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA)

Miller, J. B.·Brandon, J. A.·McKinnon, L. M.·Sabra, H. W.·Lucido, C. C.·Murcia, J. D. G.·Nations, K. A.·Payne, S. H.·Ebbert, M.·Kauwe, J. S.·Ridge, P. G.

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Abstract

BACKGROUNDSynonymous variant NC_000007.14:g.100373690T>C (rs2405442:T>C) in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) gene was previously associated with decreased risk for Alzheimers disease (AD) in genome-wide association studies, but its biological impact is largely unknown. OBJECTIVEWe hypothesized that rs2405442:T>C decreases mRNA and protein levels by destroying a ramp of slowly translated codons at the 5 end of PILRA. METHODSWe assessed rs2405442:T>C predicted effects on PILRA through quantitative polymerase chain reactions (qPCR) and enzyme-linked immunosorbent assays (ELISA) using Chinese hamster ovary (CHO) cells. RESULTSBoth mRNA (P=1.9184 x 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. CONCLUSIONSWe show that rs2405442:T>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 ContextO_LISystematic review: Genetic variants identified through genome-wide association studies often lack biological support for their association with Alzheimers disease. Although synonymous variant rs2405442:T>C in PILRA was previously reported as protective against Alzheimers disease, its effects have generally been attributed to linkage with missense variant, rs1859788:A>G. C_LIO_LIInterpretation: We show that rs2405442:T>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>C association with Alzheimers disease independent of rs1859788:A>G. C_LIO_LIFuture 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. C_LI

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Miller, J. B., Brandon, J. A., McKinnon, L. M., Sabra, H. W., Lucido, C. C., Murcia, J. D. G., Nations, K. A., Payne, S. H., Ebbert, M., Kauwe, J. S., Ridge, P. G.. 2025-01-08. Ramp sequence may explain synonymous variant association with Alzheimer's disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA). https://doi.org/10.1101/2025.01.06.631528

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