Table 1 Discovery phase: Multi-ancestry summary of known potential disease-causing variants only present in Alzheimer’s disease and related dementia cases in AoU, 100KGP and UKB

From: Biobank-scale genetic characterization of Alzheimer’s disease and related dementias across diverse ancestries

 

Gene

Position

rs ID/ClinVar ID

cDNA changes

Protein change/Splicing

Clinical significance

HGMD/Disease reported

CADD

Genetic ancestry

Zygosity

GnomAD

AoU

           
 

APP

chr21: 25891796a

rs63750066

C>T

p.A713T

Pathogenic, Likely pathogenic, VUS

CM930033, AD

26.9

EUR

Het

3.64E-05

 

PSEN1

chr14:73170945

rs63749824

C>T

p.A79V

Pathogenic, Likely pathogenic

CM981649, AD

26.1

AFR

Het

1.34E-05

 

MAPT

chr17:46024061

rs63750424

C>T

p.R406W

Pathogenic,VUS

CM981237, FTD with parkinsonism

23.9

EUR

Het

1.98E-05

 

GRN

chr17:44350757

rs777704177

G>A

p.C222Y

VUS

CM149714, AD

28.9

AMR

Het

2.24E-05

 

TARDBP

chr1:11022268a

rs80356719

G>A

p.G287S

Pathogenic, Likely pathogenic, VUS

CM081839, ALS

22.6

EUR

Het

4.32E-05

100KGP

PSEN1

chr14:73198067

rs63750900

G>A

p.R269H

Pathogenic, Likely pathogenic

CM971254, AD

29.9

EUR

Het

8.48E-06

 

TARDBP

chr1:11022268a

rs80356719

G>A

p.G287S

Pathogenic, Likely pathogenic, VUS

CM081839, ALS

22.6

EUR

Het

4.32E-05

UKB

GBA1

chr1:155237446

rs1671825414

G>T

p.F298L

Likely pathogenic

CM000164, Gaucher disease 2

23.6

EUR

Het

7.20E-06

 

GBA1

chr1:155238206

rs381427

A>C

p.V230G

Pathogenic/VUS

CM980833, Gaucher disease

22.5

EUR

Het

3.39E-06

 

GBA1

chr1:155238228

rs61748906

A>G

p.W223R

Pathogenic/Likely pathogenic/VUS

CM001166, Gaucher disease 2

28

EUR

Het

1.19E-05

 

GBA1

chr1:155238302

rs80222298

G>A

p.P198L

Likely pathogenic, VUS

CM980827, Gaucher disease

28.6

EUR

Het

8.62E-07

 

PSEN1

chr14:73170945

rs63749824

C>T

p.A79V

Pathogenic, Likely pathogenic

CM981649, AD

26.1

EUR

Het

1.10E-05

 

PSEN1

chr14:73192832

rs63750526

C>A

p.A246E

Pathogenic, Likely pathogenic

CM951075, AD

25.4

EUR

Het

9.00E-07

 

PSEN1

chr14:73198061

rs63750779

C>T

p.P267L

Likely pathogenic

CM033803, AD

25.8

EUR

Het

9.01E-07

 

PSEN1

chr14:73198067

rs63750900

G>A

p.R269H

Pathogenic, Likely pathogenic

CM971254, AD

29.9

EUR

Het

8.48E-06

 

GRN

chr17:44350449

VCV001922048.3

->CTGTGAAGACAGGGTGCACTGCTGT

p.P166fsa

Pathogenic

Not reported, FTD

34

EUR

Het

8.48E-07

 

GRN

chr17:44350801

rs63749817

G>A

c.708+1G>A

Pathogenic/Likely pathogenic

CS200794, FTD

34

EUR

Het

3.42E-06

 

GRN

chr17:44351438

rs63751177

G>A

p.W304X

Pathogenic

CM064045, FTD - CM188618, FTLD

39

AJ

Het

0

 

GRN

chr17:44352087

rs63751180

C>T

p.R418X

Pathogenic

CM062773, FTD

25.6

EUR

Het

4.50E-06

 

GRN

chr17:44352404

rs63751294

C>T

p.R493X

Pathogenic

CM064044, FTD

36

EUR

Het

1.62E-05

 

MAPT

chr17:46024061

rs63750424

C>T

p.R406W

Pathogenic, VUS

CM981237, FTD with parkinsonism

23.9

EUR

Het

1.98E-05

 

APP

chr21:25891784

rs63750264

C>T

p.V717L

Pathogenic/Likely pathogenic

CM003587, AD

26.8

EUR

Het

1.80E-06

 

APP

chr21:25891856

rs63750579

C>G

p.E693Q

Pathogenic/Likely pathogenic

CM920067, AD

27.1

EUR

Het

-

 

TBK1

chr12:64497215

rs778577820

G>C

p.D639H

VUS

CM187872, AD

22.9

EUR

Het

1.81E-06

 

TBK1

chr12:64455934

rs576726084

A>C

p.N22H

VUS

CM152626, ALS

26.4

EUR

Het

8.48E-06

 

TBK1

chr12:64474372

rs748622208

G>A

p.R228H

VUS

CM152640, ALS

34

EUR

Het

7.63E-06

 

TBK1

chr12:64488573

rs1131690783

A>-

p.E476fs

-

CD171626, MND

34

EUR

Het

2.71E-06

  1. AoU All of Us, 100KGP 100,000 Genomes Project, UKB UK Biobank, EUR European, AFR African, AMR American Admixed, AAC African Admixed, AJ Ashkenazi Jewish, CAS Central Asian, EAS Eastern Asian, SAS South Asian, MDE Middle Eastern, FIN Finnish, CAH Complex Admixture History, HGMD Human Gene Mutation Database, The frequency of gnomAD refers to the frequency in the ancestry where the variations were found. Bold variants were replicated in different databases. Disease reported refers to the disease for which the variants were previously reported. Position refers to GRCh 38.
  2. cDNA complementary DNA, VUS variant uncertain significance, Het Heterozygous, CADD Combined Annotation Dependent Depletion, AD Alzheimer’s disease, FTD frontotemporal dementia, ALS Amyotrophic lateral sclerosis, MND Motor neuron disease.
  3. aThese variants were not replicated only in cases across the diverse biobanks in the discovery phase. Clinical significance based on dbSNP, ClinVar, and ACMG guideline.
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