Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3'UTR protect against ALS.
Chen EitanAviad SianyElad BarkanTsviya OlenderKristel R van EijkMatthieu MoisseSali M K FarhanYehuda M DaninoEran YanowskiHagai Marmor-KolletNatalia RivkinNancy Sarah YacovzadaShu-Ting HungJohnathan Cooper-KnockChien-Hsiung YuCynthia LouisSeth L MastersKevin P KennaRick A A van der SpekWilliam SprovieroAhmad Al KhleifatAlfredo IacoangeliAleksey ShatunovAshley R JonesYael Elbaz-AlonYahel CohenElik ChapnikDaphna RothschildOmer WeissbrodGilad BeckElena AinbinderShifra Ben-DorSebastian WerneburgDorothy P SchaferRobert H BrownPamela J ShawPhilip Van DammeLeonard H van den BergHemali PhatnaniEran SegalJustin K IchidaAmmar Al ChalabiJan Herman Veldinknull nullnull nullEran HornsteinPublished in: Nature neuroscience (2022)
The noncoding genome is substantially larger than the protein-coding genome but has been largely unexplored by genetic association studies. Here, we performed region-based rare variant association analysis of >25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole genomes and the whole genomes of 70,403 non-ALS controls. We identified interleukin-18 receptor accessory protein (IL18RAP) 3' untranslated region (3'UTR) variants as significantly enriched in non-ALS genomes and associated with a fivefold reduced risk of developing ALS, and this was replicated in an independent cohort. These variants in the IL18RAP 3'UTR reduce mRNA stability and the binding of double-stranded RNA (dsRNA)-binding proteins. Finally, the variants of the IL18RAP 3'UTR confer a survival advantage for motor neurons because they dampen neurotoxicity of human induced pluripotent stem cell (iPSC)-derived microglia bearing an ALS-associated expansion in C9orf72, and this depends on NF-κB signaling. This study reveals genetic variants that protect against ALS by reducing neuroinflammation and emphasizes the importance of noncoding genetic association studies.
Keyphrases
- amyotrophic lateral sclerosis
- copy number
- binding protein
- genome wide
- stem cells
- traumatic brain injury
- amino acid
- endothelial cells
- gene expression
- protein protein
- lps induced
- dna methylation
- inflammatory response
- spinal cord
- small molecule
- immune response
- lipopolysaccharide induced
- diabetic rats
- blood brain barrier
- high glucose
- case control
- toll like receptor
- drug induced
- cell therapy
- pluripotent stem cells
- dna binding