Connecting the Dots: Potential of Data Integration to Identify Regulatory SNPs in Late-Onset Alzheimer's Disease GWAS Findings

... suggestive single-nucleotide polymorphisms (SNPs) reported for risk or AAO of AD (see Table S1 ). Included among these SNPs were the 28 genome-wide significant SNPs from 21 non- APOE LOAD risk loci ( PICALM, BIN1, CD33, CD2AP, MS4A4A/MS4A6E, ABCA7, EPHA1, CLU, CR1, HLA-DRB5/HLA-DRB1, PTK2B, SORL1, SLC24A4/RIN3, DSG2, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2 , and CASS4 ) [5] - [7] and 16 SNPs from novel suggestive loci identified in two GWAS of risk and AAO of LOAD ( DCHS, HRK/RNFT2, ADAMTS9, KCNV2

... remaining 394 returned scores of 16. Of those 394 variants, 34 had a RegulomeDB score of less than 3 ( Table 3 and Table S2 ), indicating a relatively high degree of evidence for potential regulatory function (likely to affect binding). Interestingly only 3 of these 34 SNPs were the reported genome-wide significant SNPs ( ZCWPW1/ rs1476679, score=1f; ABCA7 /rs3764650, score=2b; and CLU /rs1532278, score=2b), one was a reported suggestive SNP ( HRK/RNFT2 /rs17429217, score=2b), and the remaining 30 were

... chr11:85815029 rs1237999 2a PICALM region intergenic ------- AP-1 JUN upstream PICALM Jundm2 JUNB JUND FOS chr19:1046519 rs3764650 2a ABCA7 intron 13 ------- TBX22 SP1 TBX18 HNF4A TBX15 HNF4G HNF4alpha1 BHLHE40 COUPTF USF1 HNF4 USF2 COUP-TF=HNF-4 NR2F1 chr12:117295332 rs17429217 2b HRK/RNFT2 region intergenic ------- HNF4=COUP EBF1 downstream RNFT Hnf4a downstream HRK chr6:47447040 rs4715019 2b CD2AP intron 1 ------- Irx-3 POLR2A Sox15 HoxB5 Zfp105 Hoxa3 DIx1 Hoxb8 Irx6 Hoxa6 Coordinate dbSNP ID

.../SLC28A1 , and HRK/RNFT2 , also had variants with strong evidence for regulatory function with scores of 2b (1 of 6 SNPs tested), 1f (2 of 7 SNPs tested), and 2b (1 of 1 SNP tested), respectively. Of the 30 SNPs that were in LD with reported genome-wide significant variants and had high evidence of regulatory function, 10 were located in the MS4A region, including the SNP with the most evidence for regulatory function, rs667897 (RegulomeDB score=1b). RegulomeDB cites rs667897 affects binding of 21

... implicated with risk and AAO of LOAD. Of the 21 non- APOE genome-wide significant risk loci, ten ZCWPW1, CLU , ABCA7, MS4A4A/MS4A6E , PICALM, CD2AP, BIN1 , CELF1, CASS4 , and PTK2B had SNPs with functional evidence. Of the 16 suggestive novel loci, three-- HRK/RNFT2 , ADAMTS9 , and ZNF592/ALPK3/SLC28A1-- had SNPs with functional evidence. Importantly, only three of the 34 SNPs with evidence for potential regulatory function based on RegulomeDB score were the reported genome-wide significant SNPs [ ZCWPW1

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Gene: RNFT2 - ring finger protein, transmembrane 2 - (NCBI)

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