Table 2.
Analysis of the EOAD genes coding variants identified by WES
| DISCOVERY STUDY |
REPLICATION STUDY |
|||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CONTROL |
AD |
CONTROL |
AD |
|||||||||||||||
| chr:position (dbSNP142)* |
Gene | Maj/ Min allele |
Amino Acid change |
CADD_PHRED | SIFT Prediction |
Polyphen Prediction |
N Maj |
N Min |
MAF (%) |
N Maj |
N Min |
MAF (%) |
N Maj |
N Min |
MAF (%) |
N Maj |
N Min |
MAF (%) |
| 1:227071595 (c.331T>C) | PSEN2 | T/C | PSEN2:NM_000447:exon5:c.T331C:p.PhelllLeu | 25.2 | Tolerated | Possibility damaging | 214 | 0 | 0 | 261 | 1 | 0.4 | 462 | 0 | 0 | 130 | 0 | 0 |
| 14:73640435 (rs777923890) | PSEN1 | C/T | PSEN1 :uc001xnq.4:exon5:c.C500T:p.Serl67Phea,b | 10.89 | Deleterious | Benign | 214 | 0 | 0 | 261 | 1 | 0.4 | 444 | 0 | 0 | 132 | 0 | 0 |
| 21:27284211 (rsl45371658) | APP | G/C | APP:NM_001204301:exonl4:c.C1751G:p.Pro584Arg | 23.7 | Deleterious | Possibility damaging | 214 | 0 | 0 | 261 | 1 | 0.4 | 461 | 1 | 0.22 | 134 | 0 | 0 |
| 21:27369675 (c.922C>T) | APP | G/A | APP:NM_001136130:exon7:c.C922T :p.Leu308Phea | 21.7 | Tolerated | Benign | 214 | 0 | 0 | 261 | 1 | 0.4 | 413 | 1 | 0.24 | 124 | 0 | 0 |
| 21:27394195 (rs202198008) | APP | T/A | APP:NM_000484:exon6:c.A826T:p.Thr276Ser | 20.6 | Tolerated | Unknown | 214 | 0 | 0 | 261 | 1 | 0.4 | 459 | 3 | 0.65 | 131 | 1 | 0.76 |
| 21:27462388 (rs151188448) | APP | C/T | APP:NM_000484:exon3:c.G226A: p.Val76Ile | 23.4 | Tolerated | Probably damaging | 214 | 0 | 0 | 260 | 2 | 0.8 | 465 | 1 | 0.21 | 134 | 0 | 0 |
| 1:227068398 (rs111567390) | PSEN2 | G/T | PSEN2: ENST00000391872:c.G52T:p.Alal8Serc | 0.955 | Tolerated | Benign | 159 | 55 | 25.7 | 206 | 56 | 21.4 | ||||||
| 1:227071449 (rs58973334) | PSEN2 | G/A | PSEN2:NM_000447:exon5:c.G185A: p.Arg62His | 16.22 | Tolerated | Possibly damaging | 205 | 9 | 4.2 | 254 | 8 | 3.1 | ||||||
| 1:227076717 (rs138836272) | PSEN2 | G/A | PSEN2:NM_000447:exon8:c.G754A:p.Ala252Thr | 23 | Tolerated | Possibly damaging | 213 | 1 | 0.5 | 261 | 1 | 0.4 | ||||||
| 14:73626743 (rs114944042) | PSEN1 | G/A | PSEN1: ENST00000553447: p.Ala34Thrc | – | – | – | 201 | 13 | 6.1 | 254 | 8 | 3.1 | ||||||
| 14:73673178 (rsl7125721) | PSEN1 | A/G | PSEN 1: NM.000021 :exon9: c.A953G:p.Glu318Gly | 16.92 | Deleterious | Possibly damaging | 213 | 1 | 0.5 | 260 | 2 | 0.8 | ||||||
| 21:27284122 (rs112263157) | APP | T/C | APP:NM_001136129:exonll:c.A1447G:p.Ser483Gly | 18.51 | Tolerated | Benign | 208 | 6 | 2.8 | 256 | 6 | 2.3 | ||||||
| 21:27394181 (rs764406483) | APP | TGTG/T | APP:NM_001136129:exon5:c.669_67 ldel:p.Thr224del | – | – | – | 213 | 1 | 0.5 | 262 | 0 | 0 | ||||||
| 21:27512583 (rs9305282) | APP | C/G | Start Gained | – | – | – | 202 | 12 | 5.6 | 250 | 12 | 4.6 | ||||||
Summary of the variants in EOAD genes identified in the WES discovery study and resulting in alteration of the coding sequence. All variants only observed in AD cases but not in the cognitively normal controls of the WES discovery cohort were evaluated in the replication cohort. Follow-up was done by genotyping for all but 2 variants
which were Sanger sequenced due to inability to design genotyping probes. Chr, chromosome; Maj, major allele; Min, minor allele; N, number of observations; MAF, minor allele frequency. Amino acid change is depicted according to ANNOVAR [33] reference gene notations where available,
University of California Santa Cruz (UCSC)
ENSEMBL transcript notations where not available. Chromosomal positions are according to Genome Build