Table 2 Discovery phase: Multi-ancestry summary of novel 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	CADD	PP2 prediction	Genetic ancestry	Zygosity	GnomAD
AoU
	APP	chr21:25881764	Novel	G>A	p.A740V	VUS	26.7	Probably Damaging	AJ	Het	0
	APP	chr21:25911860	rs765301301	A>C	p.L597W	VUS	25.7	Probably Damaging	AFR	Het	1.47E-04
	APP	chr21:26021894	Novel	T>C	p.S271G	VUS	24.5	Benign	EUR	Het	0
	APP	chr21:25982349	rs2042464223	A>T	p.S407T	VUS	24.2	Probably Damaging	EUR	Het	3.60E-06
	APP	chr21:25982445^a	rs141331202	C>T	p.V375I	VUS	25.7	Probably Damaging	EUR	Het	3.22E-05
	APP	chr21:25982457	rs747438691	T>C	p.T371A	VUS	24.6	Possibly Damaging	AMR	Het	4.47E-05
	APP	chr21:25997360	rs749453173	G>A	p.L364F	VUS	23.9	Benign	AFR	Het	1.74E-04
	PSEN1	chr14:73170869	Novel	C>T	p.R54X	Pathogenic	36	-	AFR	Het	0
	PSEN2	chr1:226890133	rs1410382029	T>C	p.S296P	VUS	33	Probably Damaging	EUR	Het	0
	PSEN2	chr1:226891797	Novel	CT>C	p.L344X	Pathogenic	23.9	-	AMR	Het	0
	PSEN2	chr1:226888098	rs1661490243	A>G	p.H169R	VUS	26.2	Probably Damaging	EUR	Het	8.48E-07
	PSEN2	chr1:226890124	rs199689738	A>T	p.I293L	VUS	27.1	Possibly Damaging	EUR	Het	4.16E-05
	*PSEN2*	chr1:226891817	rs759669954	G>A	p.G349R	VUS	22.1	Benign	AAC	Het	6.67E-05
	GRN	chr17:44350296	rs1248058567	T>C	p.C140R	VUS	24.2	Probably Damaging	EUR	Het	1.80E-06
	GRN	chr17:44350735	rs1201429668	T>C	p.C215R	VUS	29.5	Probably Damaging	EUR	Het	1.70E-06
	GRN	chr17:44351575	Novel	A>G	p.H320R	VUS	26.2	Probably Damaging	EUR	Het	8.99E-07
	GRN	chr17:44352682	rs63750116	C>T	p.R556C	VUS	24.7	Probably Damaging	EUR	Het	7.19E-06
	MAPT	chr17:45974472	rs747085337	G>A	c.307+1G>A	-	23.3	-	EUR	Het	6.33E-06
	MAPT	chr17:45983788	Novel	AGGGGCCCCTGGAGAGGGGCCAGAGGCCC>A	p.G332LfsX64	-	27.3	-	EUR	Het	0
	MAPT	chr17:46018716	rs948573449	G>A	p.G701R	VUS	34	Probably Damaging	EUR	Het	8.10E-06
	MAPT	chr17:46024088^a	rs768841567	G>A	p.G750S	VUS	33	Probably Damaging	EUR	Het	2.20E-05
	TREM2	chr6:41161502	rs369181900	C>T	p.C51Y	VUS	27.9	Probably Damaging	EUR	Het	1.44E-05
	TREM2	chr6:41161523	Novel	C>T	p.W44X	Pathogenic	37	-	AAC	Het	0
	GBA1	chr1:155239657	rs759174705	G>T	p.P138H	VUS	22.3	Benign	EUR	Het	2.54E-06
	GBA1	chr1:155239762	rs748485792	C>T	p.G103D	VUS	20.4	Benign	EUR	Het	3.60E-06
	SNCA	chr4:89822256	rs757477802	T>C	p.Q99R	VUS	21.9	Benign	EUR	Het	1.36E-05
	TARDBP	chr1:11020491	Novel	G>A	p.M202I	VUS	22.2	Benign	AFR	Het	-
	TARDBP	chr1:11022647	Novel	G>C	p.G413A	Likely pathogenic	23.2	Probably Damaging	EUR	Het	-
	TBK1	chr12:64460226	rs748061846	A>G	p.N42S	Likely benign, VUS	22.5	Benign	AJ	Het	0
	TBK1	chr12:64480112	rs746971642	A>G	p.S268G	VUS	21.5	Possibly Damaging	EUR	Het	1.80E-06
	TBK1	chr12:64490118	rs1251738886	G>T	p.R507I	VUS	25.7	Probably Damaging	AAC	Het	2.41E-05
100KGP
	APP	chr21:25954665^a	rs779792929	A>G	p.Y407H	VUS	25.6	Probably Damaging	EUR	Het	8.31E-05
	PSEN2	chr1:226891349	rs565698726	G>A	p.D320N	VUS	21.8	Benign	EUR	Het	5.93E-06
UKB
	GBA1	chr1:155235769	rs747284798	G>A	p.R347C	VUS	31	Probably damaging	EUR	Het	8.47E-06
	GBA1	chr1:155236249	rs1057519358	A>G	p.I320T	VUS	25.3	Probably damaging	EUR	Het	8.10E-06
	GBA1	chr1:155236262	Novel	T>G	p.S316R	VUS	27.7	Probably damaging	EUR	Het	2.70E-06
	GBA1	chr1:155236471	Novel	T>C	c.1000-2A>G	-	31	-	EUR	Het	-
	GBA1	chr1:155237564	Novel	T>C	p.Y172C	VUS	28	Probably damaging	EUR	Het	4.50E-06
	GBA1	chr1:155237579	Novel	G>A	c.762-1G>A	-	26.8	-	EUR	Het	-
	GBA1	chr1:155239639	Novel	A>G	p.L57P	Likely pathogenic	28.2	Probably damaging	EUR	Het	8.99E-07
	GBA1	chr1:155239685	rs1671971599	C>T	p.A42T	VUS	21.1	Possibly damaging	EUR	Het	0
	PSEN2	chr1:226885581	rs1363866270	C>T	p.R134C	VUS	32	Probably damaging	EUR	Het	1.80E-06
	PSEN2	chr1:226885632	Novel	G>T	p.V151F	VUS	20.8	Benign	EUR	Het	8.99E-07
	PSEN2	chr1:226888846	Novel	A>T	p.Y195F	VUS	28.2	Possibly damaging	EUR	Het	8.09E-06
	PSEN2	chr1:226888864	rs200410369	A>G	p.Y201C	VUS	28.5	Probably damaging	EUR	Het	1.27E-05
	PSEN2	chr1:226891284	rs1482790603	T>C	p.M298T	VUS	25.3	Possibly damaging	EAS	Het	1.34E-04
	PSEN2	chr1:226891344	Novel	C>A	p.P318H	VUS	23.7	Possibly damaging	EUR	Het	1.80E-06
	PSEN2	chr1:226891347	Novel	A>-	p.Y319fs	-	27.9	-	EUR	Het	-
	PSEN2	chr1:226891809	rs1365789341	G>A	p.G346D	VUS	20.3	Benign	EUR	Het	8.99E-07
	*PSEN2*	chr1:226891817	rs759669954	G>A	p.G349R	VUS	22.1	Benign	EUR	Het	0
	PSEN2	chr1:226891844	Novel	A>G	p.R358G	VUS	23.4	Benign	EUR	Het	9.00E-07
	PSEN1	chr14:73170851	rs1377702483	G>A	p.E48K	VUS	23.1	Possibly damaging	EUR	Het	2.54E-06
	PSEN1	chr14:73170998	rs63750852	G>A	p.V97M	VUS	28.3	Probably damaging	EUR	Het	7.63E-06
	PSEN1	chr14:73170999	rs1356498068	T>C	p.V97A	VUS	25.6	Probably damaging	EUR	Het	8.99E-07
	PSEN1	chr14:73186896	rs63750771	T>C	p.F175S	VUS	23.7	Probably damaging	EUR	Het	9.00E-07
	PSEN1	chr14:73192754	rs763831389	G>A	p.R220Q	VUS	23.8	Possibly damaging	EUR	Het	5.93E-06
	PSEN1	chr14:73198040	Novel	C>G	p.A260G	VUS	26.8	Probably damaging	EUR	Het	9.11E-07
	PSEN1	chr14:73198052	Novel	C>G	p.P264R	Likely pathogenic	25.7	Probably damaging	EUR	Het	9.02E-07
	PSEN1	chr14:73206388	rs63750298	A>G	p.T291A	VUS	27.8	Possibly damaging	EUR	Het	5.93E-06
	PSEN1	chr14:73211836	Novel	->GCCC	p.E341fs	-	34	-	EUR	Het	-
	PSEN1	chr14:73217129	rs63750323	G>C	p.G378A	Likely pathogenic	25.4	Probably damaging	EUR	Het	5.40E-06
	PSEN1	chr14:73219155	rs1555358260	C>T	p.L424F	Likely pathogenic	25.1	Probably damaging	EUR	Het	-
	PSEN1	chr14:73219188	Novel	C>A	p.L435I	Likely pathogenic	25.8	Probably damaging	EUR	Het	1.80E-06
	PSEN1	chr14:73219194	rs764971634	A>G	p.I437V	Likely pathogenic, VUS	23	Benign	EUR	Het	6.78E-06
	PSEN1	chr14:73219254	rs1430581353	A>G	p.M457V	VUS	23.5	Probably damaging	EUR	Het	1.80E-06
	GRN	chr17:44349248	rs63751057	->GCCT	p.V28fs	-	33	-	EUR	Het	4.50E-06
	GRN	chr17:44349529	rs63751193	C>-	p.S81fs	Pathogenic	32	-	EUR	Het	8.99E-07
	GRN	chr17:44350291	rs146769257	C>A	p.T138K	VUS	24.6	Probably damaging	AFR	Het	8.96E-05
	GRN	chr17:44350303	Novel	->GGTC	p.M142fs	-	26.1	-	EUR	Het	-
	GRN	chr17:44350553	Novel	C>T	p.P192S	VUS	24.1	Probably damaging	EUR	Het	1.80E-06
	GRN	chr17:44350801	Novel	G>T	c.708+1G>T	-	32	-	EUR	Het	1.81E-06
	GRN	chr17:44351082	Novel	->TG	p.V252fs	-	25.8	-	EUR	Het	-
	GRN	chr17:44351610	Novel	A>G	p.K332E	VUS	20.3	Benign	EUR	Het	3.60E-06
	GRN	chr17:44351663	Novel	->G	p.P349fs	-	23	-	EUR	Het	8.99E-07
	GRN	chr17:44352025	Novel	G>A	p.C397Y	VUS	26.4	Probably damaging	EUR	Het	9.00E-07
	GRN	chr17:44352249	Novel	G>A	c.1413+1G>A	-	35	-	EUR	Het	9.01E-07
	GRN	chr17:44352395	rs886053006	G>A	p.V490M	VUS	25.4	Probably damaging	EUR	Het	3.39E-06
	MAPT	chr17:45962447	rs966689443	G>C	p.G37A	VUS	21.6	Probably damaging	EUR	Het	3.56E-05
	MAPT	chr17:45978420	rs139796158	C>G	p.A60G	VUS	25.1	Probably damaging	AFR	Het	5.64E-04
	MAPT	chr17:45978422	Novel	G>T	p.A61S	VUS	23.9	Probably damaging	EUR	Het	1.80E-06
	MAPT	chr17:45982886	rs940936590	C>T	p.R103W	-	20.5	-	EUR	Het	1.93E-05
	MAPT	chr17:45983453	rs2073193780	G>A	p.E292K	VUS	23.1	Possibly damaging	EUR	Het	8.50E-07
	MAPT	chr17:45983504	Novel	C>-	p.P309fs	-	22.5	-	EUR	Het	-
	MAPT	chr17:45996504	rs779901466	G>A	p.R163Q	VUS	29.3	Probably damaging	EUR	Het	9.45E-06
	MAPT	chr17:45996630	Novel	C>T	p.T205I	VUS	27.5	Probably damaging	EUR	Het	8.99E-07
	MAPT	chr17:46010394	Novel	G>A	p.G245S	VUS	33	Probably damaging	EUR	Het	3.67E-06
	MAPT	chr17:46018621	Novel	G>A	p.G245D	VUS	33	Probably damaging	EUR	Het	9.03E-07
	MAPT	chr17:46018639	Novel	A>G	p.K251R	VUS	24.7	Probably damaging	EUR	Het	-
	MAPT	chr17:46024019	rs991713081	A>G	p.I303V	VUS	26.2	Probably damaging	EUR	Het	4.50E-06
	APP	chr21:25891742	Novel	T>G	p.I600L	VUS	25.4	-	EUR	Het	5.40E-06
	APP	chr21:25905045	rs768182065	G>C	p.R517G	VUS	25.8	Probably damaging	SAS	Het	3.48E-05
	APP	chr21:25905048	rs368159818	C>T	p.D516N	VUS	27	Probably damaging	EUR	Het	5.09E-06
	APP	chr21:25911879	rs201874897	C>T	p.D460N	VUS	26.9	Probably damaging	EUR	Het	5.09E-06
	APP	chr21:25911885	rs755645885	C>T	p.G458R	VUS	27.8	Probably damaging	EUR	Het	1.19E-05
	APP	chr21:25954659	rs200500889	G>A	p.R409C	VUS	32	Probably damaging	EUR	Het	6.30E-06
	APP	chr21:25982424	rs752243493	G>A	p.P251S	VUS	26.4	Probably damaging	EUR	Het	1.10E-05
	APP	chr21:26000138	rs200539466	T>C	p.I248V	VUS	23.1	Probably damaging	EUR	Het	1.35E-05
	APP	chr21:26021858	rs772069024	C>G	p.V227L	VUS	25.4	Probably damaging	EUR	Het	8.99E-07
	APP	chr21:26021912	rs754672142	C>T	p.A209T	VUS	20.9	Probably damaging	EUR	Het	4.50E-06
	APP	chr21:26051100	rs199744129	G>A	p.P132S	VUS	27.9	Probably damaging	EUR	Het	1.70E-06
	SNCA	chr4:89726638	rs746232417	G>T	p.P90H	Likely pathogenic	24.6	Probably damaging	EUR	Het	2.71E-06
	SNCA	chr4:89822281	Novel	C>A	p.A91S	Likely pathogenic	23.8	Probably damaging	EUR	Het	1.80E-06
	TREM2	chr6:41161292	Novel	A>C	p.L121R	VUS	27	Probably damaging	EUR	Het	7.19E-06
	TREM2	chr6:41161343	Novel	T>A	p.D104V	VUS	23.7	Probably damaging	EUR	Het	8.99E-07
	APOE	chr19:44907903	rs1265280650	G>C	p.E89Q	VUS	22.3	Possibly damaging	EUR	Het	3.39E-06
	APOE	chr19:44909042	rs765845034	A>G	p.E275G	VUS	22.5	Probably damaging	EUR	Het	8.66E-07
	APOE	chr19:44909029	rs1334498236	G>A	p.D271N	VUS	22.8	Probably damaging	SAS	Het	1.25E-05
	APOE	chr19:44909171	rs121918398	G>A	p.R318H	Pathogenic/VUS	23.6	Probably damaging	EUR	Het	6.30E-06
	APOE	chr19:44908777	Novel	A>G	p.K187E	VUS	24.8	Probably damaging	EUR	Het	9.20E-07
	APOE	chr19:44908625	Novel	G>C	p.R136P	VUS	25.8	Probably damaging	EUR	Het	9.02E-07
	APOE	chr19:44907945	rs770545391	G>A	p.E103K	VUS	26.8	Probably damaging	EUR	Het	3.60E-06
	APOE	chr19:44907831	Novel	C>T	p.Q65X	Likely pathogenic	34	-	AFR	Het	2.99E-05
	TARDBP	chr1:11022581	rs1643663101	C>G	p.A391G	VUS	20.5	Benign	EUR	Het	-
	TARDBP	chr1:11013936	Novel	A>G	p.N70S	VUS	21	Benign	EUR	Het	7.19E-06
	TARDBP	chr1:11022211	Novel	A>G	p.R268G	VUS	26.2	Possibly damaging	EUR	Het	8.99E-07
	TARDBP	chr1:11022617	Novel	C>G	p.S403X	VUS	37	-	EUR	Het	-
	TBK1	chr12:64481955	rs1381192966	T>C	p.M309T	VUS	20.2	Benign	EUR	Het	1.80E-06
	TBK1	chr12:64490055	Novel	T>C	p.M486T	VUS	20.5	Benign	EUR	Het	9.01E-07
	TBK1	chr12:64464391	Novel	A>G	p.T96A	VUS	23.1	Benign	EUR	Het	5.41E-06
	TBK1	chr12:64467004	Novel	A>C	p.K154N	VUS	23.3	Probably damaging	EUR	Het	1.80E-06
	TBK1	chr12:64497733	Novel	C>T	p.T682I	VUS	23.6	Benign	EUR	Het	2.71E-06
	TBK1	chr12:64484368	rs753694282	T>C	p.I353T	VUS	23.8	Probably damaging	EUR	Het	6.30E-06
	TBK1	chr12:64484328	Novel	T>C	p.Y340H	VUS	24.1	Probably damaging	EUR	Het	3.60E-06
	TBK1	chr12:64464434	Novel	C>A	p.S110Y	VUS	24.5	Benign	EUR	Het	9.08E-07
	TBK1	chr12:64455884	Novel	C>A	p.S5Y	VUS	24.7	Probably damaging	SAS	Het	2.33E-05
	TBK1	chr12:64481994	rs751180634	A>T	p.H322L	VUS	25.2	Possibly damaging	EUR	Het	9.05E-06
	TBK1	chr12:64495773	Novel	G>C	p.R573P	VUS	26	Probably damaging	EUR	Het	9.14E-07
	TBK1	chr12:64495549	rs2040916858	G>A	p.G530R	VUS	26.7	Probably damaging	EUR	Het	8.99E-07
	TBK1	chr12:64464416	Novel	C>T	p.A104V	VUS	27.9	Probably damaging	EUR	Het	1.18E-05
	TBK1	chr12:64497966	Novel	A>G	c.2067-2A>G	-	29.3	-	EUR	Het	2.71E-06
	TBK1	chr12:64481940	rs904427940	A>T	p.D304V	VUS	29.8	Probably damaging	EUR	Het	5.94E-06
	TBK1	chr12:64464371	rs2040580815	G>A	p.C89Y	VUS	31	Possibly damaging	EUR	Het	-
	TBK1	chr12:64496367	Novel	->AAAATTTCTTC	p.R574fs	-	34	-	EUR	Het	-
	TBK1	chr12:64496951	Novel	A>-	p.Q588fs	-	34	-	EUR	Het	-

The frequency of gnomAD refers to the frequency in the ancestry where the variants were found. Bold variants were replicated in different databases. Novel in the title means it has not been reported for the disease.
cDNA complementary DNA, VUS variant uncertain significance, Het Heterozygous, CADD Combined Annotation Dependent Depletion, PP2 PolyPhen-2, Clinical significance based on dbSNP, ClinVar, and ACMG guideline. Position refers to GRCh 38.
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.
^aThese variants were not replicated only in cases across the diverse biobanks in the discovery phase. For AFR/AAC, frequencies in gnomAD for African/African American populations were used.

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Table 2 Discovery phase: Multi-ancestry summary of novel potential disease-causing variants only present in Alzheimer’s disease and related dementia cases in AoU, 100KGP and UKB

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