Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

Neumann, Alexander; Ohlei, Olena; Küçükali, Fahri; Bos, Isabelle J.; Timsina, Jigyasha; Vos, Stephanie; Prokopenko, Dmitry; Tijms, Betty M.; Andreasson, Ulf; Blennow, Kaj; Vandenberghe, Rik; Scheltens, Philip; Teunissen, Charlotte E.; Engelborghs, Sebastiaan; Frisoni, Giovanni B.; Blin, Oliver; Richardson, Jill C.; Bordet, Régis; Lleó, Alberto; Alcolea, Daniel; Popp, Julius; Marsh, Thomas W.; Gorijala, Priyanka; Clark, Christopher; Peyratout, Gwendoline; Martinez-Lage, Pablo; Tainta, Mikel; Dobson, Richard J. B.; Legido-Quigley, Cristina; Van Broeckhoven, Christine; Tanzi, Rudolph E.; ten Kate, Mara; Lill, Christina M.; Barkhof, Frederik; Cruchaga, Carlos; Lovestone, Simon; Streffer, Johannes; Zetterberg, Henrik; Visser, Pieter Jelle; Sleegers, Kristel; Bertram, Lars

doi:10.1186/s13073-023-01233-z

Table 3 Mediation models. Results from structural equation models testing the hypothesis, that SNP effects on CSF biomarker PCs would also affect AD risk

From: Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

SNP	Chr:Pos	Location	Locus	EA	EAF	R²_imp	Sex	PC1	PC2	PC3	PC4	PC5	PC	Prop	Direct	Total	Z_AD (Wightman et al.) [42]
Tau pathology/Degeneration (PC1)
rs140169162	17:30886881	Intron	MYO1D	G	0.98	0.69	m	0.02	0.10	−0.03	0.01	0.00	0.11	0.29	0.26	0.36	−1.94
rs140169162	17:30886881	Intron	MYO1D	G	0.98	0.69	f	0.52*	−0.12	−0.04	−0.01	0.00	0.35*		−1.04*	−0.69
Aβ Pathology (PC2)
rs1638675	10:119178376	Intergenic	-	A	0.57	0.89	m	0.03	0.10*	−0.03	0.00	0.00	0.10*		−0.06	0.04	−0.18
rs1638675	10:119178376	Intergenic	-	A	0.57	0.89	f	0.02	−0.04*	0.00	0.00	0.00	−0.02		0.07	0.04
Tau pathology/Degeneration & Aβ Pathology (PC1 & PC2)
rs12972156	19:45387459	Intron	APOE	C	0.74	0.98	all	−0.07*	−0.12*	0.02	0.00	0.00	−0.17*	0.65	−0.09	−0.27*	−Inf*
rs157582	19:45396219	Intron	APOE	C	0.65	1.00	all	−0.08*	−0.11*	0.01	0.00	0.00	−0.17*	0.79	−0.05	−0.22*	−Inf*
rs10119	19:45406673	3′-UTR	APOE	G	0.60	0.95	all	−0.06*	−0.10*	0.01	0.00	0.00	−0.15*	0.67	−0.07	−0.23*	−Inf*
rs429358	19:45411941	Exon	APOE	T	0.70	0.99	all	−0.09*	−0.13*	0.01	0.00	0.00	−0.21*	0.54	−0.18*	−0.39*	−Inf*
rs75627662	19:45413576	Intergenic	APOE	C	0.71	0.98	all	−0.06*	−0.10*	0.02	0.00	0.00	−0.14*	0.59	−0.10	−0.24*	−Inf*
rs157595	19:45425460	Intergenic	APOE	A	0.33	0.96	all	−0.06*	−0.09*	0.02	0.00	0.00	−0.13*	0.54	−0.11	−0.23*	−29.68*
rs111789331	19:45427125	Intergenic	APOE	T	0.73	0.95	all	−0.08*	−0.12*	0.02	0.00	0.01	−0.19*	0.57	−0.14	−0.33*	−Inf*
Injury/Inflammation (PC3)
rs7551263	1:203150756	Intron	CHI3L1	T	0.84	0.99	all	0.04	−0.01	0.05*	−0.02	0.00	0.06		−0.11	−0.05	1.21
rs114211800	5:158973225	Intron	LOC105377684	G	0.98	0.91	m	0.11	−0.08	−0.31*	0.00	0.00	−0.29*		0.27	−0.02	0.45
rs114211800	5:158973225	Intron	LOC105377684	G	0.98	0.91	f	−0.09	−0.05	0.03	0.01	0.00	−0.09		0.58	0.49
rs2302634	7:12270770	Intron	TMEM106B	T	0.58	1.00	all	−0.02	−0.01	0.07*	0.00	0.00	0.04		−0.08	−0.04	5.38*
rs56194026	15:74831534	Intergenic	ARID3B	C	0.92	0.90	m	−0.03	0.01	−0.13*	0.01	0.00	−0.15*		0.09	−0.06	−0.03
rs56194026	15:74831534	Intergenic	ARID3B	C	0.92	0.90	f	−0.01	−0.03	0.10*	0.00	0.00	0.06		−0.18	−0.12	−0.01
No evidence for mediation
rs10399931	1:203156080	Intergenic	CHI3L1	T	0.24	0.98	all	0.04	−0.03	0.02	−0.03	0.00	−0.01		0.10	0.10	0.58
rs12670437	7:76390507	Intergenic	-	G	0.98	0.87	all	−0.10	0.05	−0.01	−0.01	0.00	−0.07	0.54	−0.06	−0.14	0.22
rs145791381	9:24796757	Intergenic	-	T	0.98	0.93	all	0.00	−0.01	0.10	−0.03	0.00	0.06		−0.08	−0.02	2.20*
rs16974493	13:110307768	Intergenic	-	T	0.97	0.98	all	−0.01	0.01	0.01	0.02	0.00	0.03		−0.07	−0.03	0.34
rs150326618	14:52641990	Intergenic	-	G	0.98	0.80	all	−0.08	−0.02	−0.07	0.03	0.00	−0.15	0.19	−0.62	−0.77	−0.22
rs275844	19:48884949	Intergenic	GRIN2D	G	0.88	0.93	m	−0.07	0.02	−0.01	0.00	0.00	−0.06		0.18	0.12	−2.13*
rs275844	19:48884949	Intergenic	GRIN2D	G	0.88	0.93	f	−0.02	0.05	0.02	−0.01	0.00	0.05		−0.18	−0.13
rs8111684	19:48947326	3′-UTR	GRIN2D	G	0.26	1.00	all	0.02	0.00	−0.02	0.00	0.00	0.00	0.04	−0.01	−0.01	0.72
rs3107911	19:48964305	Intron	GRIN2D	C	0.15	0.96	all	0.02	0.00	−0.01	0.00	0.00	0.00	0.03	−0.05	−0.05	1.31

SNP RS ID, Chr:Pos Chromosome:Position Build 37, EA effect allele, SE standard error, R²_imp Imputation Quality, Sex In case of significant differences in mediation pathways between males and females based on moderated mediation models, pathway estimates are given separately for males and females, PC1-PC5 The effect of one copy of the effect allele on latent AD in SD via mediation of the biomarker PC, PC1 Tau pathology/Degeneration, PC2 Aβ Pathology, PC3 Injury/Inflammation, PC4 Non-AD Inflammation, PC5 Non-AD Synaptic Functioning, PC Joint effect of all mediation pathways via any biomarker, Prop. Proportion of mediated effect (PC/Total), Direct The effect of one copy of the effect allele on latent AD in SD not mediated by any biomarker PC, Total The joint effect of one copy of the effect allele on latent AD in SD by either mediation or direct effects, Z_AD (Wightman et al.) [42] Z test statistic based on previous GWAS of AD
^*p < 0.008

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