biostudies-literatureXicota LNational Center for Advancing Translational SciencesColumbia UniversityNICHD NIH HHSNCATS NIH HHSNIA NIH HHSUniversity of PennsylvaniaNational Institutes of HealthNational Association for Colitis and Crohn&apos;s DiseaseNIH HHSNational Institute on Aging2670-2679https://www.ebi.ac.uk/biostudies/studies/S-EPMC11032545biostudies-literatureUnknown20(4)<h4>Introduction</h4>Late-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics.<h4>Methods</h4>We conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels.<h4>Results</h4>We identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10^-9). Association of MTUS2 variants with LOAD was oAlzheimer's & dementia : the journal of the Alzheimer's AssociationWhole genome-wide sequence analysis of long-lived families (Long-Life Family Study) identifies MTUS2 gene associated with late-onset Alzheimer's disease.PMC11032545UL1 TR002373RF1 AG022018U24 AG026395P30 AG062677P30 AG066514P30 AG066515R37 AG015473R01 AG072474P30 AG066518P30 AG066519P30 AG062715P20 AG068053U01 AG051412U01 AG023744P30 AG066444U01 AG023749U01 AG023746P30 AG072958P30 AG072959U54 AG052427ADGCP50 AG008702UL1 TR002345P30 AG062421P30 AG062422UL1TR001873P30 AG010161P30 AG066546UL1 TR001414P30 AG066506P30 AG066507P30 AG062429R01 AG037212UL1 TR001857P30 AG066508P30 AG066509U01 AG023755U01 AG051406U24‐AG041689U01 AG023712P30 AG066511P30 AG066512U24 AG072122U01 AG032984U24 AG041689P20 AG068024R01 AG028786P30 AG072946P30 AG072947R01 AG015819R01AG041797U19 AG063893R01 AG026390U54 HD087011P01 AG019724P50 AG005681U24 AG021886P30 AG072931P30 AG066462P30 AG072975P20 AG068077P30 AG072976P30 AG072977R01 AG041797P30 AG072972P30 AG066468P30 AG072973P30 AG072978P30 AG072979R01 AG079280UL1 TR001873U01 AG016976P50 HD105353U19 AG068054P50 AG005133U24AG026395RC2 AG036528P30 AG066530P20 AG068082U54 HD090256U24 AG056270R01 AG017917RF1 AG066107Tilson JGriswold ARHall JRO'Bryant SKauwe JSKRosas HDAyres GCarrasquillo MMLunetta KLCuccaro MLWilliams BRosen HJMcKee ACBowen JDDeCarli CShibata DKHonig LReiman EJin LWFernandez-Hernandez VLarson EBKeator DSilverman WPLerner AJPrice JCHall KRogaeva ERosenberg RNBenchek PAlzheimer's Disease Genetic Consortium (ADGC)Gauthreaux KMStern RANudelman KDuara RKramer JHYounkin SGSano MSchneider JAAguirre ABoxer ALah JJMooney SDPulsifer MBrewer JBGalasko DRSeeley WWMathis CARizvi BYu LBartlett JVan Deerlin VMRamanan VCao CGamboa ASmith AGJones BZhao YKrinsky-McHale SKatz MJReisch JSTsuang DWJarvik GPPolk MBoeve BFAsthana SWeintraub SAlbert MSCraft SKrinsky-McHale SJCantwell LBMonuki ERafii MSTumuluru RBarber RCBurns JMChung JKunkle BWZhu CBush WSHartley SLMesulam MLupson VYassa MAWijsman EBeach TGChasse SWoltjer RLKeene CDHuentelman MJApostolova LGHynan LKlunk WEZaman SKowall NWSchupf NKuzma APKhaleeq ATrojanowski JQReitz CSwerdlow RHNadkarni NClare ICranney MKukull WAVaradarajan BEvans DADarby EHenson RWilms HChin NAMarquez DTosto GDavis BKang MIRingman JMSherva RMLaFerla FMReiman EMLee JHMapstone MNoble JChen KCrane PKWang LSFeingold EVance JMPaydarfar DChesselet MFTudorascu DLBecker JTCarlsson CMOrmsby KPetersen RCVassar RIkonomovic MDAbner EBeecham GWHakonarson HLyketsos CGFardo DWBarral SHead EVan Eldik LJFallon KBPetersen MMapstone MECulhane JMiller BLJohnson KJohnson LRyan LJordan CKaye JALai FPavlik VMassman PAnces BMPaulson HLBuxbaum JDKnebl JMoghekar AMcCurry SMMiller CAHonig LSCosentino SIbanez LGoate AMDe Jager PLSaykin AJMock CHom CFaber KMTeich AAlvarez LHernandez MPerez VBell KHarrell LEQuinn JFKofler JKStevens AAndersen SLLipton RBWelsh-Bohmer KAChui HCHyman BTGilbert JRMez JXicota LZmuda JMZhang FHuebinger RMLieberman APChen YCMartin ERDoran EWHarari OSchellenberg GDOry MSpina SPericak-Vance MARajabli FValladares OBlacker DKarydas AHanden BLFallin DMasliah EVardarajan BNPang DRoyall DRChristian BTMark LGhetti BParisi MHulette CMBurke JRWilhelmsen KCAdams PMCruchaga CAtwood CSHamilton-Nelson KLKeller BWhite DAMukherjee SWojczynski MKPerls TTVardarajan BCullum CMQuiceno MHenderson VLee JHan XNaj ACRoberson EDAndrews HJohnson SCLott ITQu LConstantino JNWheeler NMcDonough SForoud TMMinhas DSDeToledo JCBertelson JRodriguear MZhou XMarson DCKim RThyagarajan BKamboh MIBennett DAArnold SESmall SLao PAllen MHamilton RLDobbins NAndrews HFAlbin RLVan Dyck CDickson DWWoon MFairchild TJJun GChan KCFarlow MRBrickman AMVinters HVCheema ALopez OLGraff-Radford NRWisniewski TMyers AJGeorge-Hyslop PSFarrer LABirn RMMcCormick WCAlzheimer's Biomarkers Consortium‐Down Syndrome (ABC‐DS)Grabowski TMains DFagan AYashin AByrd GBulova PStrittmatter SManly JLong‐Life Family Study (LLFS)Ertekin-Taner NBarnes LLHardy JGefen TFarrell JHaines JLParisi JESultzer DTroncoso JCLeverenz JBAizenstein HJBiber SAFrosch MPGeschwind DHWilliamson JSong YMayeux RCohen ADLerch MPalmer RSchneider LSLevey AINguyen THarp JJayadev SBird TDRaj AMorris JCSmith JLaymon CSchmitt FWingo TSO'Bryant SELeung YYMasurkar AVMontine TJfalseWhole genome-wide sequence analysis of long-lived families (Long-Life Family Study) identifies MTUS2 gene associated with late-onset Alzheimer's disease.<h4>Introduction</h4>Late-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics.<h4>Methods</h4>We conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels.<h4>Results</h4>We identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10^-9). Association of MTUS2 variants with LOAD was o2024-01-01T00:00:00Z2024 Apr2026-06-02T11:24:30.023Z2026-05-27T03:07:26.734ZS-EPMC110325453838086610.1002/alz.13718