Table 3 Genes with exome-wide significant associations.

From: Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer’s disease CSF profile of neuronal injury and inflammation

   

ADNI

EMIF

Mega

Mediation

Outcome

Gene

Model

n

nsnps

ncarriers

p

n

nsnps

ncarriers

p

n

nsnps

Nsnps overlap

ncarriers

p

n

p

Adjusted for sex, age and ancestry

Tau pathology/Degeneration

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

  

Injury/Inflammation

IFFO1

Protein

127

6

4

5.1E-01

353

4

9

2.8E-06a

480

8

2

13

6.7E-07a

478

9.5E-06a

 

DTNB

Protein

127

20

3

5.5E-01

353

4

7

1.0E-03

480

22

2

10

8.3E-07a

478

1.2E-03a

 

NLRC3

Protein

127

43

11

2.5E-01

353

23

25

6.0E-05

480

59

7

36

6.0E-06

478

2.3E-03a

 

SLC22A10

LoF

127

4

2

7.7E-01

353

2

3

3.6E-04

480

5

1

5

5.0E-04

478

7.4E-03a

Aβ Pathology

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

Non-AD Inflammation

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

Non-AD Synaptic functioning

GABBR2

Protein

127

5

2

1.8E-02

353

3

2

4.3E-06a

480

8

0

4

1.6E-06a

478

8.3E-01

 

CASZ1

Protein

127

43

11

3.9E-01

353

21

29

9.1E-06

480

57

7

40

1.9E-06a

478

8.2E-01

Adjusted for sex, age, ancestry and diagnosis

Tau pathology/Degeneration

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

Injury/Inflammation

NLRC3

Protein

127

43

11

2.8E-01

353

23

25

1.2E-05

480

59

7

36

7.0E-07a

–

–

 

IFFO1

Protein

127

6

4

6.4E-01

353

4

9

9.1E-06

480

8

2

13

2.2E-06a

–

–

 

DTNB

Protein

127

20

3

4.1E-01

353

4

7

1.4E-03

480

22

2

10

2.6E-06a

–

–

 

SLC22A10

LoF

127

4

2

1

353

2

3

1.2E-04a

480

5

1

5

1.7E-04a

–

–

Aβ Pathology

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

Non-AD Inflammation

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

Non-AD Synaptic functioning

GABBR2

Protein

127

5

2

1.8E-02

353

3

2

6.3E-06

480

8

0

4

2.3E-06a

–

–

 

CASZ1

Protein

127

43

11

4.0E-01

353

21

29

9.4E-06

480

57

7

40

1.7E-06a

–

–

  1. Model Indicator whether variants were restricted to protein-coding (Protein) or loss-of-function (LoF) variants.
  2. n Sample size.
  3. nsnps Number of variants included.
  4. ncarriers Number of participants with at least one rare variant in the gene.
  5. p p value of SKAT-O test.
  6. aIndicates exome-wide significance (protein-coding: p = 5.2 * 10−6; loss-of-function: p = 1.9 * 10−4) or nominal significance (mediation: p = 0.05).
  7. nsnp overlap Number of variants present in both ADNI and EMIF.
  8. Resuls for exome-wide rare-variant and mediation analyses. Rare (MAF < 1%) protein-coding variants in 9,576 genes were tested on a gene level in the protein-coding model and 270 genes in the loss-of-function model. Each gene was associated with five principal component scores of CSF biomarkers, representing different neurodegenerative processes. P values (p) were obtained from gene-based SKAT-O tests. SMUT tested mediation on dementia symptoms (MMSE scores) via changes in the principal components. All tests were adjusted for sex, age and genetic ancestry (top group). In separate models, we additionally adjusted for diagnosis status (bottom group). Only genes with exome-wide significant association in the mega-analysis (Mega) are displayed (protein-coding: p < 5.2 * 10−6; lof: p < 1.9 * 10−4)).
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