Novel Loci for Alzheimer Disease Identified by Genome Wide Association Study in Ashkenazi Jews

Details

• Alternative Title:
  Alzheimers Dement
• Personal Author:
  Li, Donghe ; Farrell, John J ; Mez, Jesse ; Martin, Eden R. ; Bush, William S. ; Ruiz, Agustin ; Boada, Mercè ; de Rojas, Itziar ; Mayeux, Richard ; Haines, Jonathan L. ; Vance, Margaret A. Pericak ; Wang, Li-San ; Schellenberg, Gerard D. ; Lunetta, Kathryn L. ; Farrer, Lindsay A.
• Description:
  INTRODUCTION:
  
  Most Alzheimer disease (AD) loci were discovered in European ancestry individuals.
  
  METHODS:
  
  We applied principal component analysis using Gaussian mixture models and an Ashkenazi Jewish (AJ) reference genome-wide association study (GWAS) dataset to identify AJs ascertained in GWAS (n=42,682), whole genome sequencing (WGS, n=16,815) and whole exome sequencing (WES, n=20,504) datasets. Association of AD was tested genome-wide (GW) in the GWAS and WGS datasets and exome-wide (EW) in all three datasets (EW). Gene-based analyses were performed using aggregated rare variants.
  
  RESULTS:
  
  In addition to APOE, GW analyses (1,355 cases and 1,661 controls) revealed associations with TREM2 R47H (P=9.66x10−9), rs541586606 near RAB3B (P=5.01x10−8) and rs760573036 between SPOCK3 and ANXA10 (P=6.32x10−8). In EW analyses (1,504 cases and 2,047 controls), study-wide significant association was observed with rs1003710 near SMAP2 (P=1.91x10−7). A significant gene-based association was identified with GIPR (P=7.34x10−7).
  
  DISCUSSION:
  
  Our results highlight the efficacy of founder populations for AD genetic studies.
  
  
• Subjects:
  Alzheimer Disease Ethnicity Genetic Predisposition To Disease Genome-Wide Association Study Humans Jews Polymorphism, Single Nucleotide
• Keywords:
  Alzheimer Disease Ashkenazi Jews Founder Population Genome-wide Association Study
• Source:
  Alzheimers Dement. 19(12):5550-5562
• Pubmed ID:
  37260021
• Pubmed Central ID:
  PMC10689571
• Document Type:
  Journal Article
• Funding:
  R01 AG054076/AG/NIA NIH HHSUnited States/ ; HHSN268201100011I/HL/NHLBI NIH HHSUnited States/ ; P30 AG013854/AG/NIA NIH HHSUnited States/ ; HHSN268201100012C/HL/NHLBI NIH HHSUnited States/ ; P30 AG066444/AG/NIA NIH HHSUnited States/ ; RC2 HL102419/HL/NHLBI NIH HHSUnited States/ ; HHSN268201100009I/HL/NHLBI NIH HHSUnited States/ ; R01 AG018016/AG/NIA NIH HHSUnited States/ ; P30 AG010124/AG/NIA NIH HHSUnited States/ ; P50 AG023501/AG/NIA NIH HHSUnited States/ ; U01 HG006375/HG/NHGRI NIH HHSUnited States/ ; U01 AG058654/AG/NIA NIH HHSUnited States/ ; U01 HL096812/HL/NHLBI NIH HHSUnited States/ ; U01-AG062602/AG/NIA NIH HHSUnited States/ ; R01 NS017950/NS/NINDS NIH HHSUnited States/ ; P30 AG066518/AG/NIA NIH HHSUnited States/ ; U01-AG058654/AG/NIA NIH HHSUnited States/ ; U54 AG052427/AG/NIA NIH HHSUnited States/ ; U54 HG003067/HG/NHGRI NIH HHSUnited States/ ; P50 AG005142/AG/NIA NIH HHSUnited States/ ; U01-AG032984/AG/NIA NIH HHSUnited States/ ; U19-AG068753/AG/NIA NIH HHSUnited States/ ; HHSN268201100010C/HL/NHLBI NIH HHSUnited States/ ; R01 AG009029/AG/NIA NIH HHSUnited States/ ; P50 AG005131/AG/NIA NIH HHSUnited States/ ; R01 NS069719/NS/NINDS NIH HHSUnited States/ ; R01 AG015928/AG/NIA NIH HHSUnited States/ ; P01 NS026630/NS/NINDS NIH HHSUnited States/ ; P30 AG010133/AG/NIA NIH HHSUnited States/ ; U24 AG021886/AG/NIA NIH HHSUnited States/ ; R01 AG009956/AG/NIA NIH HHSUnited States/ ; HHSN268201100008C/HL/NHLBI NIH HHSUnited States/ ; U01 HL080295/HL/NHLBI NIH HHSUnited States/ ; HHSN268201500001C/HL/NHLBI NIH HHSUnited States/ ; P50 AG016574/AG/NIA NIH HHSUnited States/ ; P50 AG005146/AG/NIA NIH HHSUnited States/ ; HHSN268201100005G/HL/NHLBI NIH HHSUnited States/ ; U01 AG049507/AG/NIA NIH HHSUnited States/ ; U01 HL096917/HL/NHLBI NIH HHSUnited States/ ; HHSN268201100008I/HL/NHLBI NIH HHSUnited States/ ; U01 AG052411/AG/NIA NIH HHSUnited States/ ; R01 AG019085/AG/NIA NIH HHSUnited States/ ; U01 AG032984/AG/NIA NIH HHSUnited States/ ; U01 HG008657/HG/NHGRI NIH HHSUnited States/ ; U01 HL130114/HL/NHLBI NIH HHSUnited States/ ; HHSN268201100007C/HL/NHLBI NIH HHSUnited States/ ; HHSN268200800007C/HL/NHLBI NIH HHSUnited States/ ; P30 AG035982/AG/NIA NIH HHSUnited States/ ; P50 AG008702/AG/NIA NIH HHSUnited States/ ; HHSN268201100011C/HL/NHLBI NIH HHSUnited States/ ; RF1 AG054074/AG/NIA NIH HHSUnited States/ ; U01 AG016976/AG/NIA NIH HHSUnited States/ ; P50 NS039764/NS/NINDS NIH HHSUnited States/ ; P30 AG008051/AG/NIA NIH HHSUnited States/ ; P50 AG005681/AG/NIA NIH HHSUnited States/ ; P30 AG072978/AG/NIA NIH HHSUnited States/ ; R01 AG017917/AG/NIA NIH HHSUnited States/ ; RC2 HG005605/HG/NHGRI NIH HHSUnited States/ ; P50 AG047270/AG/NIA NIH HHSUnited States/ ; R56 AG051876/AG/NIA NIH HHSUnited States/ ; U01 HL096902/HL/NHLBI NIH HHSUnited States/ ; P30 AG013846/AG/NIA NIH HHSUnited States/ ; R01 AG028786/AG/NIA NIH HHSUnited States/ ; N01HC55222/HL/NHLBI NIH HHSUnited States/ ; U54 HG003273/HG/NHGRI NIH HHSUnited States/ ; R01 AG049607/AG/NIA NIH HHSUnited States/ ; UF1 AG047133/AG/NIA NIH HHSUnited States/ ; U01 AG057659/AG/NIA NIH HHSUnited States/ ; RF1 AG054023/AG/NIA NIH HHSUnited States/ ; P50 AG005136/AG/NIA NIH HHSUnited States/ ; P30 AG012300/AG/NIA NIH HHSUnited States/ ; NU38 CK000480/CK/NCEZID CDC HHSUnited States/ ; N01HC85086/HL/NHLBI NIH HHSUnited States/ ; R01 HL105756/HL/NHLBI NIH HHSUnited States/ ; U19 AG024904/AG/NIA NIH HHSUnited States/ ; U01 AG062943/AG/NIA NIH HHSUnited States/ ; RF1 AG051504/AG/NIA NIH HHSUnited States/ ; P50 AG016573/AG/NIA NIH HHSUnited States/ ; P50 AG047266/AG/NIA NIH HHSUnited States/ ; RF1 AG058066/AG/NIA NIH HHSUnited States/ ; RF1-AG057519/AG/NIA NIH HHSUnited States/ ; HHSN268201100006C/HL/NHLBI NIH HHSUnited States/ ; U24 AG041689/AG/NIA NIH HHSUnited States/ ; P50 AG016570/AG/NIA NIH HHSUnited States/ ; P50 AG005134/AG/NIA NIH HHSUnited States/ ; P30 AG008017/AG/NIA NIH HHSUnited States/ ; HHSN268201200036C/HL/NHLBI NIH HHSUnited States/ ; P30 AG010161/AG/NIA NIH HHSUnited States/ ; R01 AG033193/AG/NIA NIH HHSUnited States/ ; R01-AG048927/AG/NIA NIH HHSUnited States/ ; U01 AG058589/AG/NIA NIH HHSUnited States/ ; P50 AG025688/AG/NIA NIH HHSUnited States/ ; HHSN268201100005I/HL/NHLBI NIH HHSUnited States/ ; R01 AG032990/AG/NIA NIH HHSUnited States/ ; R37 AG015473/AG/NIA NIH HHSUnited States/ ; U01 NS041588/NS/NINDS NIH HHSUnited States/ ; R01 NS080820/NS/NINDS NIH HHSUnited States/ ; HHSN268201500001I/HL/NHLBI NIH HHSUnited States/ ; U01 AG049508/AG/NIA NIH HHSUnited States/ ; P50 AG008012/AG/NIA NIH HHSUnited States/ ; U01 AG052410/AG/NIA NIH HHSUnited States/ ; U01 HL096814/HL/NHLBI NIH HHSUnited States/ ; P50 AG005133/AG/NIA NIH HHSUnited States/ ; U01 AG006781/AG/NIA NIH HHSUnited States/ ; R01 AG041797/AG/NIA NIH HHSUnited States/ ; K23 AG030944/AG/NIA NIH HHSUnited States/ ; RC4 AG039085/AG/NIA NIH HHSUnited States/ ; U01 AG062602/AG/NIA NIH HHSUnited States/ ; R01 NS029993/NS/NINDS NIH HHSUnited States/ ; R01 AG021547/AG/NIA NIH HHSUnited States/ ; P50 AG005138/AG/NIA NIH HHSUnited States/ ; R01 AG048927/AG/NIA NIH HHSUnited States/ ; U54 HG003079/HG/NHGRI NIH HHSUnited States/ ; R01 AG019757/AG/NIA NIH HHSUnited States/ ; U01 AG052409/AG/NIA NIH HHSUnited States/ ; U01 AG046139/AG/NIA NIH HHSUnited States/ ; R01 AG033040/AG/NIA NIH HHSUnited States/ ; RF1 AG054052/AG/NIA NIH HHSUnited States/ ; P30 AG072977/AG/NIA NIH HHSUnited States/ ; R01 AG020098/AG/NIA NIH HHSUnited States/ ; N01HC85082/HL/NHLBI NIH HHSUnited States/ ; R01 HL070825/HL/NHLBI NIH HHSUnited States/ ; N01HC85083/HL/NHLBI NIH HHSUnited States/ ; R01 AG027944/AG/NIA NIH HHSUnited States/ ; HHSN268201100005C/HL/NHLBI NIH HHSUnited States/ ; N01HC25195/HL/NHLBI NIH HHSUnited States/ ; U54-AG052427/AG/NIA NIH HHSUnited States/ ; R01 AG025259/AG/NIA NIH HHSUnited States/ ; HHSN268201100009C/HL/NHLBI NIH HHSUnited States/ ; P50 AG047366/AG/NIA NIH HHSUnited States/ ; RF1 AG057519/AG/NIA NIH HHSUnited States/ ; U01 HL096899/HL/NHLBI NIH HHSUnited States/ ; HHSN268201100007I/HL/NHLBI NIH HHSUnited States/ ; RF1 AG015473/AG/NIA NIH HHSUnited States/ ; U01 AG049506/AG/NIA NIH HHSUnited States/ ; U01 HG004610/HG/NHGRI NIH HHSUnited States/ ; R01 AG021136/AG/NIA NIH HHSUnited States/ ; P30 AG010129/AG/NIA NIH HHSUnited States/ ; WT_/Wellcome TrustUnited Kingdom/ ; R01 AG011101/AG/NIA NIH HHSUnited States/ ; P30 AG019610/AG/NIA NIH HHSUnited States/ ; R01 AG017919/AG/NIA NIH HHSUnited States/ ; U01 AG058635/AG/NIA NIH HHSUnited States/ ; P30-AG072878/AG/NIA NIH HHSUnited States/ ; N01HC85079/HL/NHLBI NIH HHSUnited States/ ; R01 AG023629/AG/NIA NIH HHSUnited States/ ; R01 AG031272/AG/NIA NIH HHSUnited States/ ; P30 AG028383/AG/NIA NIH HHSUnited States/ ; N01HC85080/HL/NHLBI NIH HHSUnited States/ ; P50 AG033514/AG/NIA NIH HHSUnited States/ ; R01 AG011380/AG/NIA NIH HHSUnited States/ ; P50 NS071674/NS/NINDS NIH HHSUnited States/ ; U19 AG068753/AG/NIA NIH HHSUnited States/ ; RF1 AG058267/AG/NIA NIH HHSUnited States/ ; R01 AG015819/AG/NIA NIH HHSUnited States/ ; N01HC85081/HL/NHLBI NIH HHSUnited States/ ; U01 AG049505/AG/NIA NIH HHSUnited States/
• Volume:
  19
• Issue:
  12
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:9523c544da98c97b760d6afd917a3a66c2e3499844defbfe2745b3da73aecb3939a5e01c2f7b87c54f1e6b4464d3d7e40d82b7c5188750b525109013220ccc61
• Download URL:
  https://stacks.cdc.gov/view/cdc/136221/cdc_136221_DS1.pdf
• File Type:
  [PDF - 802.28 KB ]