Background
Results
CLUresequencing
Stage I: Flanders-Belgian AD cohort | Stage II: Lille AD cohort | Stage II: Toronto AD cohort | Stage III: Caribbean Hispanic AD cohort | |
---|---|---|---|---|
Total number of subjects | 1930 | 2182 | 573 | 1045 |
AD patients | 1057 | 1465 | 323 | 520 |
Mean AAO (years) (SD) | 74.9 ± 8.9 | 69.5 ± 8.2 | 75.3 ± 9.7 | 79.7 ± 8.6 |
Women (%) | 692 (65.5) | 969 (66.1) | 178 (55.1) | 369 (71.0) |
At least one APOE ε4 allele (%) | 565 (53.5) | 852 (58.2) | 182 (56.3) | 207 (39.9) |
Control individuals | 873 | 717 | 250 | 525 |
Mean AAI (years) (SD) | 65.1 ± 14.9 | 74.0 ± 8.0 | 73.0 ± 10.2 | 78.9 ± 6.5 |
Women (%) | 501 (57.4) | 447 (62.3) | 149 (60.0) | 358 (68.2) |
At least one APOE ε4 allele (%) | 235 (26.9) | 145 (20.2) | 60 (24.0) | 126 (24.0) |
Stage I: Flanders-Belgium AD cohort | |||||||||
---|---|---|---|---|---|---|---|---|---|
Gene locationa | DNAb | Proteinc | dbSNP | Total number | MAF AD | MAF C | Protein location | PolyPhen (PSIC) | SIFT |
Exon 5 | c.924G > A | p.A309T | 3 | 0.0018 (1) | β-chain | benign (1.07) | tolerated (0.65) | ||
Exon 6 | c.1012C > T | p.R338W | 2 | 0.0012 (2) | β-chain | probable (2.37) | not tolerated (0.00) | ||
Exon 6 | c.1034C > T | p.T345M | 1 | 0.0006 (2) | β-chain | possible (1.56) | tolerated (0.09) | ||
Exon 7 | c.1105A > C | p.N369H | rs9331936 | 2 | 0.0012 | β-chain | possible (1.56) | tolerated (0.15) | |
Exon 7 | c.1138G > A | p.D380N | rs9331938 | 1 | 0.0006 | β-chain | benign (0.32) | tolerated (0.36) | |
Exon 7 | c.1319C > T | p.T440M | 1 | 0.0006 | β-chain | possible (1.75) | not tolerated (0.01) | ||
Exon 8 | c.1333_1341del | p.T445_D447 del | 3 | 0.0018 (1) | β-chain | ||||
Exon 8 | c.1343C > T | p.S448L | rs13494 | 1 | 0.0006 | β-chain | benign (0.73) | tolerated (0.23) | |
Exon 8 | c.1349T > G | p.V450G | 1 | 0.0006 | β-chain | benign (1.42) | tolerated (0.15) | ||
Exon 1 | c.48C > A | p.S16R | 11 | 0.0029 (5 AD) | 0.0046 (6 C) (3) | extra AA isoform 2 | benign (1.13) | not tolerated (0.00) | |
Exon 1 | c.111C > A | p.H37Q | 4 | 0.0012 (2 AD) | 0.0015 (2 C) | extra AA isoform 2 | possible (1.80) | not tolerated (0.00) | |
Exon 5 | c.701G > A | p.R234H | 3 | 0.0012 (2 AD) | 0.0008 (1 C) (3) | α-chain | possible (1.64) | tolerated (0.15) | |
Exon 5 | c.764C > T | p.T255I | rs4127629 | 11 | 0.0029 (5 AD) | 0.0046 (6 C) | α-chain | benign (0.31) | tolerated (0.29) |
Exon 5 | c.965T > C | p.P322L | 9 | 0.0029 (5 AD) | 0.0030 (4 C) | β-chain | possible (1.96) | tolerated (0.25) | |
Exon 7 | c.1153G > A | p.V385I | 3 | 0.0006 (1 AD) | 0.0015 (2 C) | β-chain | benign (0.15) | tolerated (0.40) | |
Exon 5 | c.703G > A | p.A235T | 1 | 0.0008 | α-chain | benign (1.18) | tolerated (0.16) | ||
Exon 5 | c.797G > A | p.R266Q | 1 | 0.0008 | α-chain | benign (0.27) | tolerated (0.67) | ||
Exon 6 | c.994G > A | p.D332N | 1 | 0.0008 | β-chain | benign (0.04) | tolerated (0.1) | ||
Exon 7 | c.1268G > A | p.R423Q | 1 | 0.0008 | β-chain | benign (0.33) | tolerated (0.54) | ||
Exon 7 | c.1298A > C | p.Q433P | 1 | 0.0008 | β-chain | benign (0.41) | tolerated (0.13) |
Association analyses of rare CLUvariants
Stage II: Lille AD cohort | |||||||||
---|---|---|---|---|---|---|---|---|---|
Gene locationa | DNAb | Proteinc | dbSNP | Total number | MAF AD | MAF C | Protein location | PolyPhen (PSIC) | SIFT |
Exon 5 | c.908insA | p.I303NfsX13 | 1 | 0.0004 | β-chain | ||||
Exon 6 | c.1012C > T | p.R338W | 1 | 0.0004 | β-chain | probable (2.37) | not tolerated (0.00) | ||
Exon 7 | c.1105A > C | p.N369H | rs9331936 | 6 | 0.0023 | β-chain | possible (1.56) | tolerated (0.15) | |
Exon 8 | c.1333_1341del | p.T445_D447del | 3 | 0.0011 | β-chain | ||||
Exon 8 | c.1343C > T | p.S448L | rs13494 | 1 | 0.0004 | β-chain | benign (0.73) | tolerated (0.23) | |
Exon 8 | c.1358G > A | p.G453S | rs34627536 | 1 | 0.0004 | β-chain | benign (0.39) | ||
Exon 5 | c.965T > C | p.P322L | 5 | 0.0015 (4 AD) | 0.0008 (1 C) | β-chain | possible (1.96) | tolerated (0.25) | |
Exon 7 | c.1138G > A | p.D380N | rs9331938 | 5 | 0.0015 (4 AD) | 0.0008 (1 C) | β-chain | benign (0.32) | tolerated (0.36) |
Exon 7 | c.1310G > A | p.R437Q | 1 | 0.0008 | β-chain | benign (0.700) | |||
Stage II: Toronto AD cohort
| |||||||||
Gene location
a
|
DNA
b
|
Protein
c
|
dbSNP
|
Total Number
|
MAF AD
|
MAF C
|
Protein location
|
PolyPhen (PSIC)
|
SIFT
|
Exon 7 | c.1138G > A | p.D380N | rs9331938 | 1 | 0.0016 | β-chain | benign (0.322) | tolerated (0.36) | |
Exon 8 | c.1333_1341del | p.T445_D447del | 1 | 0.0016 | β-chain | ||||
Exon 7 | c.1105A > C | p.N369H | rs9331936 | 3 | 0.0033 (2 AD) | 0.0022 (1 C) | β-chain | possibly (1.557) | tolerated (0.15) |
Exon 8 | c.1343C > T | p.S448L | rs13494 | 3 | 0.0033 (2 AD) | 0.0022 (1 C) | β-chain | benign (0.73) | tolerated (0.23) |
Total chromosome number | Rare genetic variants | ||||
---|---|---|---|---|---|
AD | C | AD (%) | C (%) | OR [95% CI] | |
Flanders-Belgian (this study) | 1698 | 1318 | 21 (1.2) | 9 (0.7) | 1.82 [0.8-3.39] |
Lille (this study) | 2610 | 1220 | 21 (0.8) | 3 (0.2) | 3.29 [0.98-11.05] |
Toronto (this study) | 612 | 462 | 6 (1.0) | 2 (0.4) | 2.28 [0.46-11.33] |
Portugal (Guerreiro et al.) 14 | 806 | 470 | 9 (1.1) | 2 (0.4) | 2.64 [0.57-12.28] |
UK (Guerreiro et al.) 14 | 892 | 1264 | 2 (0.2) | 2 (0.2) | 1.42 [0.20-10.09] |
US-Caucasian (Tycko et al.) 15 | 106 | 86 | 1 (0.9) | 3 (3.5) | 0.26 [0.03-2.58] |
Summary
| 6724 | 4820 | 60 (0.9) | 21 (0.4) | 1.96 [1.18-3.25] |
pMH = 0.009 | |||||
pwoolf = 0.551 |
Stage III: Caribbean Hispanic AD cohort | |||||||||
---|---|---|---|---|---|---|---|---|---|
Gene locationa | DNAb | Proteinc | dbSNP | Total number | MAF AD | MAF C | Protein location | PolyPhen (PSIC) | SIFT |
Exon 5 | c.965T > C | p.P322L | 2 | 0.0022 | β-chain | possible (1.96) | tolerated (0.25) | ||
Exon 6 | c.991G > A | p.D331N | 2 | 0.0022 | β-chain | benign (0.119) | tolerated (0.28) | ||
Exon 7 | c.1291G > C | p.E431Q | 1 | 0.0011 | β-chain | benign (0.133) | tolerated (0.35) | ||
Exon 7 | c.1105A > C | p.N369H* | rs9331936 | 155 | 0.08 (84 AD) | 0.07 (71 C) | β-chain | possible (1.56) | tolerated (0.00) |
Exon 7 | c.1138G > A | p.D380N* | rs9331938 | 35 | 0.01 (13 AD) | 0.02 (22 C) | β-chain | benign(0.32) | tolerated (0.36) |
Exon 8 | c.1343C > T | p.S448L* | rs13494 | 27 | 0.01 (13 AD) | 0.01 (14 C) | β-chain | benign(0.73) | tolerated (0.23) |
Exon 6 | c.1004C > T | p.T335I | 1 | 0.0010 | β-chain | benign (1.077) | tolerated (0.64) | ||
Exon 7 | c.1153G > A | p.V385I | 1 | 0.0010 | β-chain | benign (0.150) | tolerated (0.4) |
Common CLUassociation analysis
(A) Allelic associations in stage I and II AD cohorts
| |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Belgian-Flanders | Lille | Toronto | |||||||||||
Allele | AD (total) | C (total) | OR [95% CI] |
p
| AD (total) | C (total) | OR [95% CI] |
p
| AD (total) | C (total) | OR [95% CI] |
p
| |
rs867230 | T | 0.63 (1259) | 0.59 (952) | 0.074 (1) | 0.66 (1736) | 0.62 (742) |
0.022
(1)
| 0.60 (367) | 0.63 (307) | 0.288 (1) | |||
Intron 1 | G | 0.37 (752) | 0.41 (670) | 0.82 [0.70-0.96] |
0.012
(2)
| 0.34 (904) | 0.38 (456) | 0.89 [0.76-1.04] | 0.144 (2) | 0.40 (247) | 0.37 (181) | 1.04 [0.80-1.36] | 0.771 (2) |
rs1532278 | G | 0.63 (1308) | 0.61 (1006) |
< 0.01
(1)
| 0.675 (1789) | 0.628 (764) |
0.004
(1)
| 0.62 (383) | 0.62 (301) | 0.996 (1) | |||
Intron 3 | A | 0.37 (770) | 0.40 (656) | 0.83 [0.71-0.97] |
0.019
(2)
| 0.325 (861) | 0.372 (452) | 0.83 [0.71-0.97] |
0.02
(2)
| 0.38 (233) | 0.38 (183) | 1.27 [0.97-1.64] | 0.078 (2) |
rs11136000 | G | 0.65 (1232) | 0.61 (990) |
0.034
(1)
| 0.66 (1707) | 0.628 (764) | 0.195 (1) | 0.61 (372) | 0.63 (299) | 0.645 (1) | |||
Intron 3 | A | 0.35 (676) | 0.39 (630) | 0.79 [0.68-0.93] |
0.004
(2)
| 0.34 (875) | 0.372 (452) | 0.93 [0.79-1.10] | 0.400 (2) | 0.39 (236) | 0.37 (179) | 1.00 [0.77-1.31] | 0.986 (2) |
rs9331908 | G | 0.66 (1389) | 0.69 (1161) | 0.055 (1) | 0.62 (1712) | 0.66 (841) |
0.036
(1)
| 0.66 (416) | 0.69 (338) | 0.297 (1) | |||
Intron 4 | A | 0.34 (713) | 0.31 (521) | 1.18 [1.01-1.39] |
0.035
(2)
| 0.38 (1046) | 0.35 (443) | 1.12 [0.96-1.30] | 0.156 (2) | 0.34 (214) | 0.31 (152) | 1.20 [0.91-1.56] | 0.198 (2) |
rs7982 | C | 0.63 (1228) | 0.61 (1005) | 0.191 (1) | 0.67 (1780) | 0.63 (804) |
0.022
(1)
| 0.62 (374) | 0.60 (295) | 0.434 (1) | |||
Exon 5 | T | 0.37 (734) | 0.40 (657) | 0.85 [0.73-0.99] |
0.037
(2)
| 0.33 (884) | 0.37 (470) | 0.89 [0.76-1.03] | 0.124 (2) | 0.38 (234) | 0.36 (167) | 1.16 [0.89-1.52] | 0.273 (2) |
(B) Meta-analysis of stage I and II AD cohorts
| |||||||||||||
Allele
|
Summary OR
|
p
MH
|
p
Bonf
|
p
woolf'
| |||||||||
rs867230 | T | ||||||||||||
Intron 1 | G | 0.88 [0.79-0.97] |
0.013
| 0.065 | 0.311 | ||||||||
rs1532278 | G | ||||||||||||
Intron 3 | A | 0.85 [0.77-0.94] |
0.001
|
0.005
| 0.648 | ||||||||
rs11136000 | G | ||||||||||||
Intron 3 | A | 0.88 [0.79-0.97] |
0.013
| 0.065 | 0.206 | ||||||||
rs9331908 | G | ||||||||||||
Intron 4 | A | 1.16 [1.04-1.28] |
0.006
|
0.030
| 0.824 | ||||||||
rs7982 | C | ||||||||||||
Exon 5 | T | 0.89 [0.80-0.98] |
0.023
| 0.115 | 0.448 |