Table 3 Mega-analysis: carrier frequency, effect sizes, median age at onset and attributable fraction

From: Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

 

Mega-analysis

Carrier frequency

OR (95% CI)

Median age at onset (IQR)

Attributable fraction

 

Gene

Group

No. variant/no. carriers

EOAD/LOAD/controls, %

Case/control

EOAD/control

LOAD/control

EOAD/LOAD, %

Primary analysis

SORL1

LOF + REVEL ≥ 50

212/418

2.75/1.51/0.68

2.5 (2.0–3.0)

3.3 (2.6–4.1)

2.0 (1.6–2.5)

65 (59–73)

1.91/0.75

—Missense (REVEL 50–100)

161/354

2.02/1.31/0.66

2.1 (1.7–2.5)

2.5 (2.0–3.2)

1.8 (1.4–2.3)

67 (59–74)

1.22/0.58

—LOF

51/68

0.78/0.21/0.02

19.8 (11.9–32.7)

40.7 (12.5–133)

11.3 (3.3–38.3)

62 (56–69)

0.76/0.19

TREM2

LOF + REVEL ≥ 25

26/441

2.27/1.90/0.75

2.8 (2.3–3.5)

3.3 (2.6–4.3)

2.6 (2.1–3.3)

69 (62–75)

1.58/1.17

LOF + REVEL ≥ 25 (refined)

25/404

2.22/1.77/0.62

3.1 (2.6–3.8)

3.8 (2.9–4.9)

2.8 (2.2–3.6)

68 (62–75)

1.63/1.15

—Missense (REVEL 25–100)

14/377

2.06/1.63/0.59

3.0 (2.5–3.8)

3.7 (2.8–4.9)

2.7 (2.1–3.6)

68 (62–75)

1.50/1.04

—LOF

12/66

0.21/0.29/0.16

2.1 (1.2–3.4)

1.7 (0.8–3.5)

2.2 (1.3–3.9)

71 (63–76)

0.09/0.16

—LOF (refined)

11/29

0.16/0.16/0.02

5.6 (2.6–12.1)

5.8 (1.7–19)

5.4 (1.8–16.8)

71 (63–74)

0.13/0.13

ABCA7

LOF + REVEL ≥ 25

351/1,489

6.18/5.04/3.90

1.4 (1.3–1.6)

1.6 (1.4–1.9)

1.3 (1.2–1.5)

69 (61–78)

2.40/1.29

—Missense (REVEL 25–100)

302/1,372

5.58/4.65/3.63

1.4 (1.3–1.6)

1.6 (1.4–1.8)

1.3 (1.2–1.5)

69 (62–78)

2.06/1.18

—LOF

49/119

0.62/0.39/0.27

1.7 (1.1–2.4)

2.2 (1.4–3.5)

1.4 (0.9–2.1)

67 (57–74)

0.34/0.11

ATP8B4

LOF + REVEL ≥ 25

94/850

3.56/3.08/2.09

1.4 (1.2–1.6)

1.5 (1.3–1.8)

1.4 (1.2–1.6)

70 (61–78)

1.24/0.84

—Missense (REVEL 25–100)

74/797

3.35/2.93/1.93

1.5 (1.3–1.7)

1.6 (1.3–1.9)

1.4 (1.2–1.7)

70 (62–78)

1.20/0.84

—LOF

20/54

0.21/0.16/0.16

1.1 (0.6–1.9)

1.2 (0.6–2.4)

1.0 (0.5–1.8)

70 (59–78)

0.03/−0.01

ABCA1

LOF + REVEL ≥ 75

122/442

1.91/1.50/1.13

1.6 (1.3–2.0)

1.9 (1.5–2.5)

1.5 (1.2–1.9)

70 (60–76)

0.91/0.48

LOF + REVEL ≥ 75 (refined)

120/282

1.52/1.10/0.52

2.4 (1.9–3.1)

2.9 (2.2–4.0)

2.2 (1.6–2.9)

70 (59–76)

1.01/0.60

—Missense (REVEL 75–100)

95/395

1.63/1.32/1.05

1.5 (1.2–1.8)

1.7 (1.3–2.2)

1.4 (1.1–1.8)

70 (61–76)

0.68/0.37

—Missense (REVEL 75–100 (refined))

93/235

1.24/0.92/0.44

2.3 (1.7–3.0)

2.7 (1.9–3.8)

2.1 (1.5–2.8)

70 (59–76)

0.78/0.48

—LOF

27/47

0.28/0.18/0.08

3.5 (1.9–6.4)

4.7 (2.2–10.3)

2.8 (1.3–6.1)

67 (59–77)

0.22/0.11

ADAM10

LOF + REVEL ≥ 50

19/22

0.23/0.05/0.02

4.7 (2.0–10.8)

9.0 (2.9–28)

2.2 (0.5–8.2)

63 (60–68)

0.20/0.03

GWAS-targeted analysis

RIN3

LOF + REVEL ≥ 50

23/583

2.67/2.10/1.62

1.4 (1.2–1.7)

1.6 (1.3–2.0)

1.3 (1.1–1.6)

70 (59–79)

1.04/0.46

—Missense (REVEL 50–100)

17/577

2.62/2.08/1.61

1.4 (1.2–1.7)

1.6 (1.3–2.0)

1.3 (1.1–1.6)

70 (59–79)

1.01/0.45

—LOF

6/8

0.06/0.03/0.01

2.1 (0.5–9.3)

2.9 (0.5–18.0)

1.7 (0.3–10.3)

69 (57–86)

0.04/0.01

CLU

LOF + REVEL ≥ 25

24/26

0.23/0.09/0.03

3.6 (1.6–8.3)

5.8 (2.0–17.1)

2.5 (0.8–7.6)

63 (58–73)

0.19/0.05

—Missense (REVEL 25–100)

14/16

0.12/0.06/0.03

2.6 (0.9–7.5)

3.6 (0.9–13.6)

2.1 (0.6–8.0)

68 (58–76)

0.08/0.03

—LOF

10/10

0.12/0.03/0.01

7.3 (1.9–27.2)

14.2 (2.9–470.4)

3.8 (0.6–122.4)

63 (59–68)

0.11/0.02

ZCWPW1

LOF

11/15

0.15/0.05/0.01

5.0 (1.9–13.5)

9.1 (2.0–42.0)

2.9 (0.8–14.7)

63 (58–81)

0.14/0.03

ACE

LOF + REVEL ≥ 75

38/99

0.60/0.39/0.20

2.0 (1.3–2.9)

2.4 (1.5–4.1)

1.7 (1.0–2.7)

67 (60–75)

0.35/0.16

—Missense (REVEL 75–100)

10/49

0.33/0.22/0.07

3.2 (1.7–5.7)

3.9 (1.8–8.8)

2.7 (1.3–5.9)

66 (61–72)

0.24/0.14

—LOF

28/50

0.27/0.16/0.14

1.4 (0.8–2.4)

1.7 (0.9–3.4)

1.2 (0.6–2.2)

70 (55–76)

0.11/0.02

  1. For each gene, the AD association statistics are shown for the variant deleteriousness threshold with the most evidence for AD association in the meta-analysis (bold). For genes with sufficient carriers, signals are shown for LOF and missense variants separately (regular text). Individual variants contributing to the burden were validated in a multistage analysis (Supplementary Table 16 and Methods), which resulted in the construction of a refined burden for TREM2 (one variant removed) and ABCA1 (two variants removed). The attributable fraction of a gene is an estimate of the fraction of EOAD and LOAD cases in this sample that have become part of this dataset due to carrying a rare damaging variant in the respective gene (Methods). Note that several variants were excluded from this analysis (that is, due to differential missingness) that would otherwise have been included in the burden. See section 2 of the Supplementary Note for a gene-specific discussion of the variants that contribute to the association with AD and Supplementary Data for the list of variants considered in the burden analysis. Genes shown in bold: the variant burden was significantly associated with AD in the meta-analysis (Holm–Bonferroni <0.05; Table 1). P values for the mega-analysis are shown in Supplementary Table 15.
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