{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:16:35Z","timestamp":1790626595346,"version":"4.1.0"},"reference-count":70,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T00:00:00Z","timestamp":1637020800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T00:00:00Z","timestamp":1637020800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Psychiatry"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Established genetic risk factors for Alzheimer\u2019s disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (<jats:italic>n<\/jats:italic>\u2009=\u2009209), mild cognitive impairment (<jats:italic>n<\/jats:italic>\u2009=\u20091449) or normal cognition (<jats:italic>n<\/jats:italic>\u2009=\u2009985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (<jats:italic>SHARPIN<\/jats:italic>) gene was associated with entorhinal cortical thickness (<jats:italic>p<\/jats:italic>\u2009=\u20095.0\u2009\u00d7\u200910<jats:sup>\u22129<\/jats:sup>) and hippocampal volume (<jats:italic>p<\/jats:italic>\u2009=\u20095.1\u2009\u00d7\u200910<jats:sup>\u221212<\/jats:sup>). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-\u03b2 accumulation (<jats:italic>p<\/jats:italic>\u2009=\u20090.03) and measures of memory (<jats:italic>p<\/jats:italic>\u2009=\u20091.0\u2009\u00d7\u200910<jats:sup>\u22124<\/jats:sup>) and executive function (<jats:italic>p<\/jats:italic>\u2009=\u20090.04). We also found significant association of other <jats:italic>SHARPIN<\/jats:italic> variants with hippocampal volume in the Alzheimer\u2019s Disease Neuroimaging Initiative (rs3417062, <jats:italic>p<\/jats:italic>\u2009=\u20094.1\u2009\u00d7\u200910<jats:sup>\u22126<\/jats:sup>) and AddNeuroMed (rs138412600, <jats:italic>p<\/jats:italic>\u2009=\u20095.9\u2009\u00d7\u200910<jats:sup>\u22125<\/jats:sup>) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-\u03baB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.<\/jats:p>","DOI":"10.1038\/s41398-021-01680-5","type":"journal-article","created":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T08:03:02Z","timestamp":1637049782000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A missense variant in SHARPIN mediates Alzheimer\u2019s disease-specific brain damages"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9098-2858","authenticated-orcid":false,"given":"Jun Young","family":"Park","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7057-745X","authenticated-orcid":false,"given":"Dongsoo","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jang Jae","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungsoo","family":"Gim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8639-5060","authenticated-orcid":false,"given":"Tamil Iniyan","family":"Gunasekaran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyu Yeong","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarang","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ah Ra","family":"Do","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyeon","family":"Jo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juhong","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyungtaek","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donghe","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanghun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoowon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Immanuel","family":"Dhanasingh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suparna","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seula","family":"Keum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jee Hye","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gyun Jee","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee","family":"Sael","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangmyung","family":"Rhee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Lovestone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunae","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Hwan","family":"Moon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byeong C.","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"SangYun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1376-8532","authenticated-orcid":false,"given":"Andrew J.","family":"Saykin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwangsik","family":"Nho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Haeng","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5533-4225","authenticated-orcid":false,"given":"Lindsay A.","family":"Farrer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3230-8697","authenticated-orcid":false,"given":"Gyungah R.","family":"Jun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5751-5089","authenticated-orcid":false,"given":"Sungho","family":"Won","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4144-8162","authenticated-orcid":false,"given":"Kun Ho","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,16]]},"reference":[{"key":"1680_CR1","doi-asserted-by":"crossref","unstructured":"2018 Alzheimer\u2019s disease facts and figures. Alzheimer\u2019s Dementia. 2018;14:367\u2013429.","DOI":"10.1016\/j.jalz.2018.02.001"},{"key":"1680_CR2","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1001\/archpsyc.63.2.168","volume":"63","author":"M Gatz","year":"2006","unstructured":"Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006;63:168\u201374.","journal-title":"Arch Gen Psychiatry"},{"key":"1680_CR3","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1126\/science.8346443","volume":"261","author":"EH Corder","year":"1993","unstructured":"Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer\u2019s disease in late onset families. Science. 1993;261:921\u20133.","journal-title":"Science"},{"key":"1680_CR4","doi-asserted-by":"publisher","first-page":"1977","DOI":"10.1073\/pnas.90.5.1977","volume":"90","author":"WJ Strittmatter","year":"1993","unstructured":"Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA. 1993;90:1977\u201381.","journal-title":"Proc Natl Acad Sci USA"},{"key":"1680_CR5","doi-asserted-by":"publisher","first-page":"e79771","DOI":"10.1371\/journal.pone.0079771","volume":"8","author":"PG Ridge","year":"2013","unstructured":"Ridge PG, Mukherjee S, Crane PK, Kauwe JS, Alzheimer\u2019s Disease Genetics C. Alzheimer\u2019s disease: analyzing the missing heritability. PLoS ONE. 2013;8:e79771.","journal-title":"PLoS ONE"},{"key":"1680_CR6","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-018-0221-8","volume":"8","author":"H Stocker","year":"2018","unstructured":"Stocker H, M\u00f6llers T, Perna L, Brenner H. The genetic risk of Alzheimer\u2019s disease beyond APOE \u03b54: systematic review of Alzheimer\u2019s genetic risk scores. Transl Psychiatry. 2018;8:166.","journal-title":"Transl Psychiatry"},{"key":"1680_CR7","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1038\/s41588-019-0358-2","volume":"51","author":"BW Kunkle","year":"2019","unstructured":"Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, et al. Genetic meta-analysis of diagnosed Alzheimer\u2019s disease identifies new risk loci and implicates A\u03b2, tau, immunity and lipid processing. Nat Genet. 2019;51:414\u201330.","journal-title":"Nat Genet"},{"key":"1680_CR8","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1016\/S1474-4422(19)30435-1","volume":"19","author":"SJ Andrews","year":"2020","unstructured":"Andrews SJ, Fulton-Howard B, Goate A. Interpretation of risk loci from genome-wide association studies of Alzheimer\u2019s disease. Lancet Neurol. 2020;19:326\u201335.","journal-title":"Lancet Neurol"},{"key":"1680_CR9","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1038\/nrg2760","volume":"11","author":"NA Rosenberg","year":"2010","unstructured":"Rosenberg NA, Huang L, Jewett EM, Szpiech ZA, Jankovic I, Boehnke M. Genome-wide association studies in diverse populations. Nat Rev Genet. 2010;11:356\u201366.","journal-title":"Nat Rev Genet"},{"key":"1680_CR10","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.ajhg.2009.11.016","volume":"86","author":"N Zaitlen","year":"2010","unstructured":"Zaitlen N, Pa\u015faniuc B, Gur T, Ziv E, Halperin E. Leveraging genetic variability across populations for the identification of causal variants. Am J Hum Genet. 2010;86:23\u201333.","journal-title":"Am J Hum Genet"},{"key":"1680_CR11","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1038\/ejhg.2011.219","volume":"20","author":"X Wang","year":"2012","unstructured":"Wang X, Liu X, Sim X, Xu H, Khor CC, Ong RT, et al. A statistical method for region-based meta-analysis of genome-wide association studies in genetically diverse populations. Eur J Hum Genet. 2012;20:469\u201375.","journal-title":"Eur J Hum Genet"},{"key":"1680_CR12","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1001\/jama.2013.2973","volume":"309","author":"C Reitz","year":"2013","unstructured":"Reitz C, Jun G, Naj A, Rajbhandary R, Vardarajan BN, Wang LS, et al. Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E 4,and the risk of late-onset Alzheimer disease in African Americans. JAMA. 2013;309:1483\u201392.","journal-title":"JAMA"},{"key":"1680_CR13","first-page":"320","volume":"68","author":"JH Lee","year":"2011","unstructured":"Lee JH, Cheng R, Barral S, Reitz C, Medrano M, Lantigua R, et al. Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals. Arch Neurol. 2011;68:320\u20138.","journal-title":"Arch Neurol"},{"key":"1680_CR14","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1002\/acn3.537","volume":"5","author":"BN Vardarajan","year":"2018","unstructured":"Vardarajan BN, Barral S, Jaworski J, Beecham GW, Blue E, Tosto G, et al. Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer\u2019s disease. Ann Clin Transl Neurol. 2018;5:406\u201317.","journal-title":"Ann Clin Transl Neurol"},{"key":"1680_CR15","doi-asserted-by":"publisher","first-page":"e58618","DOI":"10.1371\/journal.pone.0058618","volume":"8","author":"A Miyashita","year":"2013","unstructured":"Miyashita A, Koike A, Jun G, Wang LS, Takahashi S, Matsubara E, et al. SORL1 is genetically associated with late-onset Alzheimer\u2019s disease in Japanese, Koreans and Caucasians. PLoS ONE. 2013;8:e58618.","journal-title":"PLoS ONE"},{"key":"1680_CR16","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s10020-019-0090-5","volume":"25","author":"Y Asanomi","year":"2019","unstructured":"Asanomi Y, Shigemizu D, Miyashita A, Mitsumori R, Mori T, Hara N, et al. A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer\u2019s disease. Mol Med. 2019;25:20.","journal-title":"Mol Med"},{"key":"1680_CR17","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.1073\/pnas.1715554115","volume":"115","author":"X Zhou","year":"2018","unstructured":"Zhou X, Chen Y, Mok KY, Zhao Q, Chen K, Chen Y, et al. Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer\u2019s disease pathogenesis. Proc Natl Acad Sci USA. 2018;115:1697\u2013706.","journal-title":"Proc Natl Acad Sci USA"},{"key":"1680_CR18","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1016\/j.jalz.2016.12.012","volume":"13","author":"GR Jun","year":"2017","unstructured":"Jun GR, Chung J, Mez J, Barber R, Beecham GW, Bennett DA, et al. Transethnic genome-wide scan identifies novel Alzheimer\u2019s disease loci. Alzheimers Dement. 2017;13:727\u201338.","journal-title":"Alzheimers Dement"},{"key":"1680_CR19","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1016\/j.tics.2013.08.007","volume":"17","author":"MN Braskie","year":"2013","unstructured":"Braskie MN, Thompson PM. Understanding cognitive deficits in Alzheimer\u2019s disease based on neuroimaging findings. Trends Cogn Sci. 2013;17:510\u20136.","journal-title":"Trends Cogn Sci"},{"key":"1680_CR20","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.jalz.2013.01.008","volume":"10","author":"R Sherva","year":"2014","unstructured":"Sherva R, Tripodis Y, Bennett DA, Chibnik LB, Crane PK, de Jager PL, et al. Genome-wide association study of the rate of cognitive decline in Alzheimer\u2019s disease. Alzheimer\u2019s Dement: J Alzheimer\u2019s Assoc. 2014;10:45\u201352.","journal-title":"Alzheimer\u2019s Dement: J Alzheimer\u2019s Assoc"},{"key":"1680_CR21","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1038\/s41586-018-0571-7","volume":"562","author":"LT Elliott","year":"2018","unstructured":"Elliott LT, Sharp K, Alfaro-Almagro F, Shi S, Miller KL, Douaud G, et al. Genome-wide association studies of brain imaging phenotypes in UK Biobank. Nature. 2018;562:210\u20136.","journal-title":"Nature"},{"key":"1680_CR22","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1602\/neurorx.1.2.213","volume":"1","author":"K Blennow","year":"2004","unstructured":"Blennow K. Cerebrospinal fluid protein biomarkers for Alzheimer\u2019s disease. NeuroRx. 2004;1:213\u201325.","journal-title":"NeuroRx"},{"key":"1680_CR23","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/s42003-018-0254-9","volume":"2","author":"J Xu","year":"2019","unstructured":"Xu J, Patassini S, Rustogi N, Riba-Garcia I, Hale BD, Phillips AM, et al. Regional protein expression in human Alzheimer\u2019s brain correlates with disease severity. Commun Biol. 2019;2:43.","journal-title":"Commun Biol"},{"key":"1680_CR24","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1016\/j.jalz.2015.05.009","volume":"11","author":"AJ Saykin","year":"2015","unstructured":"Saykin AJ, Shen L, Yao X, Kim S, Nho K, Risacher SL, et al. Genetic studies of quantitative MCI and AD phenotypes in ADNI: progress, opportunities, and plans. Alzheimers Dement. 2015;11:792\u2013814.","journal-title":"Alzheimers Dement"},{"key":"1680_CR25","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1086\/519795","volume":"81","author":"S Purcell","year":"2007","unstructured":"Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559\u201375.","journal-title":"Am J Hum Genet"},{"key":"1680_CR26","doi-asserted-by":"publisher","first-page":"2851","DOI":"10.1093\/bioinformatics\/bty180","volume":"34","author":"YE Song","year":"2018","unstructured":"Song YE, Lee S, Park K, Elston RC, Yang HJ, Won S. ONETOOL for the analysis of family-based big data. Bioinformatics. 2018;34:2851\u20133.","journal-title":"Bioinformatics"},{"key":"1680_CR27","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1038\/ng1847","volume":"38","author":"AL Price","year":"2006","unstructured":"Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38:904\u20139.","journal-title":"Nat Genet"},{"key":"1680_CR28","doi-asserted-by":"publisher","first-page":"2336","DOI":"10.1093\/bioinformatics\/btq419","volume":"26","author":"RJ Pruim","year":"2010","unstructured":"Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010;26:2336\u20137.","journal-title":"Bioinformatics"},{"key":"1680_CR29","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1212\/WNL.0b013e3181cb3e25","volume":"74","author":"RC Petersen","year":"2010","unstructured":"Petersen RC, Aisen PS, Beckett LA, Donohue MC, Gamst AC, Harvey DJ, et al. Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI): clinical characterization. Neurology. 2010;74:201\u20139.","journal-title":"Neurology"},{"key":"1680_CR30","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1111\/j.1749-6632.2009.05064.x","volume":"1180","author":"S Lovestone","year":"2009","unstructured":"Lovestone S, Francis P, Kloszewska I, Mecocci P, Simmons A, Soininen H, et al. AddNeuroMed\u2013the European collaboration for the discovery of novel biomarkers for Alzheimer\u2019s disease. Ann N. Y Acad Sci. 2009;1180:36\u201346.","journal-title":"Ann N. Y Acad Sci"},{"key":"1680_CR31","doi-asserted-by":"publisher","first-page":"e1004219","DOI":"10.1371\/journal.pcbi.1004219","volume":"11","author":"CA de Leeuw","year":"2015","unstructured":"de Leeuw CA, Mooij JM, Heskes T, Posthuma D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol. 2015;11:e1004219.","journal-title":"PLoS Comput Biol"},{"key":"1680_CR32","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01261-5","volume":"8","author":"K Watanabe","year":"2017","unstructured":"Watanabe K, Taskesen E, van Bochoven A, Posthuma D. Functional mapping and annotation of genetic associations with FUMA. Nat Commun. 2017;8:1826.","journal-title":"Nat Commun"},{"key":"1680_CR33","doi-asserted-by":"crossref","unstructured":"Bolin JH, Hayes, Andrew F. (2013). Introduction to Mediation, Moderation, and Conditional Process Analysis: A Regression-Based Approach. New York, NY: The Guilford Press. Journal of Educational Measurement, 2014;51:335\u20137.","DOI":"10.1111\/jedm.12050"},{"key":"1680_CR34","doi-asserted-by":"publisher","first-page":"723","DOI":"10.2967\/jnumed.112.107185","volume":"54","author":"GA Becker","year":"2013","unstructured":"Becker GA, Ichise M, Barthel H, Luthardt J, Patt M, Seese A, et al. PET quantification of 18F-florbetaben binding to \u03b2-amyloid deposits in human brains. J Nucl Med. 2013;54:723\u201331.","journal-title":"J Nucl Med"},{"key":"1680_CR35","doi-asserted-by":"publisher","unstructured":"Choi KY, Lee JJ, Gunasekaran TI, Kang S, Lee W, Jeong J, et al. APOE promoter polymorphism-219T\/G is an effect modifier of the influence of APOE \u03b54 on Alzheimer\u2019s disease risk in a multiracial sample. J Clin Med. 2019;8, https:\/\/doi.org\/10.3390\/jcm8081236.","DOI":"10.3390\/jcm8081236"},{"key":"1680_CR36","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.3346\/jkms.2010.25.7.1071","volume":"25","author":"H-J Ahn","year":"2010","unstructured":"Ahn H-J, Chin J, Park A, Lee BH, Suh MK, Seo SW, et al. Seoul Neuropsychological Screening Battery-dementia version (SNSB-D): a useful tool for assessing and monitoring cognitive impairments in dementia patients. J Korean Med Sci. 2010;25:1071\u20136.","journal-title":"J Korean Med Sci"},{"key":"1680_CR37","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-37832-9","volume":"9","author":"S Moon","year":"2019","unstructured":"Moon S, Kim YJ, Han S, Hwang MY, Shin DM, Park MY, et al. The Korea Biobank Array: design and identification of coding variants associated with blood biochemical traits. Sci Rep. 2019;9:1382.","journal-title":"Sci Rep."},{"key":"1680_CR38","unstructured":"Karczewski KJ, et al. Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes. BioRxiv. 2019;531210."},{"key":"1680_CR39","doi-asserted-by":"publisher","first-page":"1514","DOI":"10.3390\/ijms20061514","volume":"20","author":"V Giau","year":"2019","unstructured":"Giau V, Senanarong V, Bagyinszky E, An S, Kim S. Analysis of 50 neurodegenerative genes in clinically diagnosed early-onset Alzheimer\u2019s disease. Int J Mol Sci. 2019;20:1514.","journal-title":"Int J Mol Sci"},{"key":"1680_CR40","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.celrep.2017.09.031","volume":"21","author":"J Liu","year":"2017","unstructured":"Liu J, Wang Y, Gong Y, Fu T, Hu S, Zhou Z, et al. Structural insights into SHARPIN-mediated activation of HOIP for the linear ubiquitin chain assembly. Cell Rep. 2017;21:27\u201336.","journal-title":"Cell Rep."},{"key":"1680_CR41","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1038\/ng.2802","volume":"45","author":"JC Lambert","year":"2013","unstructured":"Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer\u2019s disease. Nat Genet. 2013;45:1452\u20138.","journal-title":"Nat Genet"},{"key":"1680_CR42","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-018-0150-6","volume":"8","author":"RE Marioni","year":"2018","unstructured":"Marioni RE, Harris SE, Zhang Q, McRae AF, Hagenaars SP, Hill WD, et al. GWAS on family history of Alzheimer\u2019s disease. Transl Psychiatry. 2018;8:99.","journal-title":"Transl Psychiatry"},{"key":"1680_CR43","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1002\/ana.23644","volume":"72","author":"SA Melville","year":"2012","unstructured":"Melville SA, Buros J, Parrado AR, Vardarajan B, Logue MW, Shen L, et al. Multiple loci influencing hippocampal degeneration identified by genome scan. Ann Neurol. 2012;72:65\u201375.","journal-title":"Ann Neurol"},{"key":"1680_CR44","unstructured":"Kang S, et al. East Asian-specific novel loci associated with late-onset Alzheimer\u2019s disease: the GARD cohort Genome-wide study. medRxiv. 2020; 2020.07.02.20145557."},{"key":"1680_CR45","doi-asserted-by":"publisher","first-page":"3737","DOI":"10.1002\/hbm.25083","volume":"41","author":"S Soheili-Nezhad","year":"2020","unstructured":"Soheili-Nezhad S, Jahanshad N, Guelfi S, Khosrowabadi R, Saykin AJ, Thompson PM, et al. Imaging genomics discovery of a new risk variant for Alzheimer\u2019s disease in the postsynaptic SHARPIN gene. Hum Brain Mapp. 2020;41:3737\u201348.","journal-title":"Hum Brain Mapp"},{"key":"1680_CR46","unstructured":"de Rojas I, et al. Common variants in Alzheimer\u2019s disease: novel association of six genetic variants with AD and risk stratification by polygenic risk scores. medRxiv. 2020;19012021."},{"key":"1680_CR47","doi-asserted-by":"publisher","first-page":"75","DOI":"10.3233\/JAD-2001-3111","volume":"3","author":"DJ Selkoe","year":"2001","unstructured":"Selkoe DJ. Alzheimer\u2019s disease results from the cerebral accumulation and cytotoxicity of amyloid \u00df-protein. J Alzheimer\u2019s Dis. 2001;3:75\u201380.","journal-title":"J Alzheimer\u2019s Dis"},{"key":"1680_CR48","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-57525-6","volume":"10","author":"YH Jung","year":"2020","unstructured":"Jung YH, Park S, Jang H, Cho SH, Kim SJ, Kim JP, et al. Frontal-executive dysfunction affects dementia conversion in patients with amnestic mild cognitive impairment. Sci Rep. 2020;10:772.","journal-title":"Sci Rep."},{"key":"1680_CR49","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1093\/hmg\/5.7.985","volume":"5","author":"R Sherrington","year":"1996","unstructured":"Sherrington R, Froelich S, Sorbi S, Campion D, Chi H, Rogaeva EA, et al. Alzheimer\u2019s disease associated with mutations in presenilin 2 is rare and variably penetrant. Hum Mol Genet. 1996;5:985\u20138.","journal-title":"Hum Mol Genet"},{"key":"1680_CR50","doi-asserted-by":"publisher","first-page":"e1007306","DOI":"10.1371\/journal.pgen.1007306","volume":"14","author":"D Lancour","year":"2018","unstructured":"Lancour D, Naj A, Mayeux R, Haines JL, Pericak-Vance MA, Schellenberg GD, et al. One for all and all for One: Improving replication of genetic studies through network diffusion. PLoS Genet. 2018;14:e1007306.","journal-title":"PLoS Genet"},{"key":"1680_CR51","doi-asserted-by":"publisher","first-page":"3741","DOI":"10.1038\/emboj.2011.264","volume":"30","author":"J Niu","year":"2011","unstructured":"Niu J, Shi Y, Iwai K, Wu ZH. LUBAC regulates NF-\u03baB activation upon genotoxic stress by promoting linear ubiquitination of NEMO. Embo J. 2011;30:3741\u201353.","journal-title":"Embo J"},{"key":"1680_CR52","doi-asserted-by":"publisher","first-page":"399","DOI":"10.3389\/fimmu.2017.00399","volume":"8","author":"I Aksentijevich","year":"2017","unstructured":"Aksentijevich I, Zhou Q. NF-\u03baB pathway in autoinflammatory diseases: dysregulation of protein modifications by ubiquitin defines a new category of autoinflammatory diseases. Front Immunol. 2017;8:399.","journal-title":"Front Immunol"},{"key":"1680_CR53","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1038\/nature09815","volume":"471","author":"F Tokunaga","year":"2011","unstructured":"Tokunaga F, Nakagawa T, Nakahara M, Saeki Y, Taniguchi M, Sakata S, et al. SHARPIN is a component of the NF-\u03baB-activating linear ubiquitin chain assembly complex. Nature. 2011;471:633\u20136.","journal-title":"Nature"},{"key":"1680_CR54","doi-asserted-by":"publisher","first-page":"a001271","DOI":"10.1101\/cshperspect.a001271","volume":"1","author":"B Kaltschmidt","year":"2009","unstructured":"Kaltschmidt B, Kaltschmidt C. NF-kappaB in the nervous system. Cold Spring Harb Perspect Biol. 2009;1:a001271.","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"1680_CR55","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1006\/mcne.2000.0940","volume":"17","author":"S Lim","year":"2001","unstructured":"Lim S, Sala C, Yoon J, Park S, Kuroda S, Sheng M, et al. Sharpin, a novel postsynaptic density protein that directly interacts with the shank family of proteins. Mol Cell Neurosci. 2001;17:385\u201397.","journal-title":"Mol Cell Neurosci"},{"key":"1680_CR56","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/s41583-018-0093-1","volume":"20","author":"J Yuan","year":"2019","unstructured":"Yuan J, Amin P, Ofengeim D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci. 2019;20:19\u201333.","journal-title":"Nat Rev Neurosci"},{"key":"1680_CR57","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.neurobiolaging.2020.02.001","volume":"93","author":"D Krishnan","year":"2020","unstructured":"Krishnan D, Menon RN, Mathuranath PS, Gopala S. A novel role for SHARPIN in amyloid-\u03b2 phagocytosis and inflammation by peripheral blood-derived macrophages in Alzheimer\u2019s disease. Neurobiol Aging. 2020;93:131\u201341.","journal-title":"Neurobiol Aging"},{"key":"1680_CR58","doi-asserted-by":"publisher","first-page":"1859","DOI":"10.1038\/s41380-018-0112-7","volume":"25","author":"JC Bis","year":"2020","unstructured":"Bis JC, Jian X, Kunkle BW, Chen Y, Hamilton-Nelson KL, Bush WS, et al. Whole exome sequencing study identifies novel rare and common Alzheimer\u2019s-Associated variants involved in immune response and transcriptional regulation. Molecular Psychiatry. 2020;25:1859\u201375.","journal-title":"Molecular Psychiatry"},{"key":"1680_CR59","doi-asserted-by":"publisher","first-page":"1635","DOI":"10.3233\/JAD-181085","volume":"68","author":"H Patel","year":"2019","unstructured":"Patel H, Dobson RJB, Newhouse SJ. A meta-analysis of Alzheimer\u2019s disease brain transcriptomic data. J Alzheimers Dis. 2019;68:1635\u201356.","journal-title":"J Alzheimers Dis"},{"key":"1680_CR60","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1038\/s41586-019-1195-2","volume":"570","author":"H Mathys","year":"2019","unstructured":"Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, et al. Single-cell transcriptomic analysis of Alzheimer\u2019s disease. Nature. 2019;570:332\u20137.","journal-title":"Nature"},{"key":"1680_CR61","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1038\/nrn.2017.170","volume":"19","author":"MJ Devine","year":"2018","unstructured":"Devine MJ, Kittler JT. Mitochondria at the neuronal presynapse in health and disease. Nat Rev Neurosci. 2018;19:63\u201380.","journal-title":"Nat Rev Neurosci"},{"key":"1680_CR62","doi-asserted-by":"publisher","first-page":"18670","DOI":"10.1073\/pnas.1006586107","volume":"107","author":"H Du","year":"2010","unstructured":"Du H, Guo L, Yan S, Sosunov AA, McKhann GM, Yan SS. Early deficits in synaptic mitochondria in an Alzheimer\u2019s disease mouse model. Proc Natl Acad Sci USA. 2010;107:18670\u20135.","journal-title":"Proc Natl Acad Sci USA"},{"key":"1680_CR63","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/j.tins.2013.03.002","volume":"36","author":"B DuBoff","year":"2013","unstructured":"DuBoff B, Feany M, G\u00f6tz J. Why size matters - balancing mitochondrial dynamics in Alzheimer\u2019s disease. Trends Neurosci. 2013;36:325\u201335.","journal-title":"Trends Neurosci"},{"key":"1680_CR64","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1212\/WNL.45.3.482","volume":"45","author":"WD Parker Jr.","year":"1995","unstructured":"Parker WD Jr., Parks JK. Cytochrome c oxidase in Alzheimer\u2019s disease brain: purification and characterization. Neurology. 1995;45:482\u20136.","journal-title":"Neurology"},{"key":"1680_CR65","doi-asserted-by":"publisher","first-page":"2264","DOI":"10.1038\/s41386-018-0144-3","volume":"43","author":"R Bi","year":"2018","unstructured":"Bi R, Zhang W, Zhang DF, Xu M, Fan Y, Hu QX, et al. Genetic association of the cytochrome c oxidase-related genes with Alzheimer\u2019s disease in Han Chinese. Neuropsychopharmacology. 2018;43:2264\u201376.","journal-title":"Neuropsychopharmacology"},{"key":"1680_CR66","doi-asserted-by":"publisher","first-page":"236","DOI":"10.3389\/fnhum.2016.00236","volume":"10","author":"SH Tadayon","year":"2016","unstructured":"Tadayon SH, Vaziri-Pashkam M, Kahali P, Ansari Dezfouli M, Abbassian A. Common genetic variant in VIT Is associated with human brain asymmetry. Front Hum Neurosci. 2016;10:236.","journal-title":"Front Hum Neurosci"},{"key":"1680_CR67","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.pharmthera.2003.12.002","volume":"101","author":"JL Steiger","year":"2004","unstructured":"Steiger JL, Russek SJ. GABAA receptors: building the bridge between subunit mRNAs, their promoters, and cognate transcription factors. Pharm Ther. 2004;101:259\u201381.","journal-title":"Pharm Ther"},{"key":"1680_CR68","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1007\/s10571-016-0347-2","volume":"37","author":"Z Ma","year":"2017","unstructured":"Ma Z, Niu B, Shi Z, Li J, Wang J, Zhang F, et al. Genetic polymorphism of GABRR2 modulates individuals\u2019 general cognitive ability in healthy Chinese Han People. Cell Mol Neurobiol. 2017;37:93\u2013100.","journal-title":"Cell Mol Neurobiol"},{"key":"1680_CR69","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1038\/ng.3073","volume":"46","author":"ML Gatza","year":"2014","unstructured":"Gatza ML, Silva GO, Parker JS, Fan C, Perou CM. An integrated genomics approach identifies drivers of proliferation in luminal-subtype human breast cancer. Nat Genet. 2014;46:1051\u20139.","journal-title":"Nat Genet"},{"key":"1680_CR70","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1038\/nrd.2018.71","volume":"17","author":"PA Boriack-Sjodin","year":"2018","unstructured":"Boriack-Sjodin PA, Ribich S, Copeland RA. RNA-modifying proteins as anticancer drug targets. Nat Rev Drug Discov. 2018;17:435\u201353.","journal-title":"Nat Rev Drug Discov"}],"container-title":["Translational Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41398-021-01680-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-021-01680-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-021-01680-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T15:38:44Z","timestamp":1669909124000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41398-021-01680-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,16]]},"references-count":70,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["1680"],"URL":"https:\/\/doi.org\/10.1038\/s41398-021-01680-5","relation":{},"ISSN":["2158-3188"],"issn-type":[{"value":"2158-3188","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,16]]},"assertion":[{"value":"10 November 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 August 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 August 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 November 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"590"}}