Pleiotropic action of genetic variation in ZNF804A on brain structure: a meta-analysis of magnetic resonance imaging studies

Figures & data

Figure 1 Flowchart of the selection process.

Table 1 General characteristics of the included studies

Study	Year of publication	Population (n)	Age (years)	Gender (male, n)	Ancestry	Medication	Genotype distribution
							AA	AC	CC	HWE
Gray matter
Lencz et al^Citation7	2010	HC (39)	34.4	19	Caucasian	–	18	14	7	Yes
Donohoe et al^Citation13	2011	SZ (70)	40.4	46	Caucasian	Yes	27	30	13	Yes
		HC (38)	32.5	20	Caucasian	–	19	14	5	Yes
Voineskos et al^Citation14	2011	HC (62)	37.4	40	Caucasian	–	23	33	6	Yes
Cousijn et al^Citation15	2012	HC (892)	22.8	369	Caucasian	–	297	434	160	Yes
Wassink et al^Citation8	2012	SZ (335)	31.7	248	Caucasian	Yes	126	165	44	NS
		HC (198)	30.7	103	Caucasian	–	69	105	24	NS
Wei et al^Citation16	2012	SZ (80)	26.6	45	Chinese	Yes	15	46	19	Yes
		HC (69)	25.4	39	Chinese	–	22	35	12	Yes
Bergmann et al^Citation17	2013	SZ (82)	34.2	49	Caucasian	Yes	NS	NS	NS	NS
		HC (152)	35.9	79	Caucasian	–	NS	NS	NS	NS
Schultz et al^Citation18	2014	SZ (55)	29.3	NS	Caucasian	Yes	20	35 (AC + CC)		NS
		HC (40)	27.3	NS	Caucasian	–	15	25 (AC + CC)		NS
Cousijn et al^Citation20	2015	HC (1,300)	22.9	43	Caucasian	–	NS	NS	NS	NS
Nenadic et al^Citation19	2015	SZ (62)	31.6	44	Caucasian	Yes	23	33	6	Yes
		HC (54)	29.5	29	Caucasian	–	19	28	7	Yes
Wei et al^Citation21	2015	SZ (59)	26.3	31	Chinese	No	26	16	17	Yes
		HC (60)	25.6	33	Chinese	–	38	12	10	Yes
White matter
Voineskos et al^Citation14	2011	HC (62)	37.4	40	Caucasian	–	23	33	6	Yes
Kuswanto et al^Citation22	2012	SZ (125)	34.3	90	Chinese	Yes	26	53	32	Yes
		HC (75)	31.9	48	Chinese	–	11	37	19	Yes
Sprooten et al^Citation23	2012	HC (50)	22.7	25	Caucasian	–	19	24	7	Yes
Wei et al^Citation24	2013	SZ (100)	26.5	53	Chinese	Yes	18	58	24	Yes
		HC (69)	25.4	39	Chinese	–	22	35	12	Yes
Ikuta et al^Citation25	2014	HC (107)	31.8	56	Caucasian	–	43	42	22	NS
Mallas et al^Citation26	2016	SZ (63)	33.8	50	Mixed	Yes	27	28	8	Yes
		HC (124)	35.8	67	Mixed	–	59	51	14	Yes
Zhang et al^Citation27	2016	HC (87)	27.6	68	Chinese	–	23	43	21	Yes

Abbreviations: HC, healthy control; SZ, schizophrenia.

Table 2 Scanning characteristics and quality assessment of the included studies

Study	Year of publication	fMRI information Tesla FWHM (mm) Task Indices				Quality
Gray matter
Lencz et al^Citation7	2010	1.5	NS	None	GM, WM, CSF	High
Donohoe et al^Citation13	2011	1.5	8	None	GM	High
Voineskos et al^Citation14	2011	1.5	NS	None	CT	High
Cousijn et al^Citation15	2012	1.5, 3.0	8	None	GM, WM	High
Wassink et al^Citation8	2012	1.5	NS	None	GM, WM, CSF	High
Wei et al^Citation16	2012	1.5	12	None	WM	High
Bergmann et al^Citation17	2013	1.5	30	None	CT	Medium
Schultz et al^Citation18	2014	1.5	NS	None	CT, CF	Medium
Cousijn et al^Citation20	2015	1.5	NS	None	GM, WM	Medium
Nenadic et al^Citation19	2015	1.5	12	None	GM, WM	High
Wei et al^Citation21	2015	1.5	10	None	CT, CSA, CV	High
White matter
Voineskos et al^Citation14	2011	1.5	None	None	FA	High
Kuswanto et al^Citation22	2012	3	None	None	FA	High
Sprooten et al^Citation23	2012	1.5	None	None	FA, MD	High
Wei et al^Citation24	2013	1.5	None	None	FA, MD	High
Ikuta et al^Citation25	2014	3	None	None	FA	High
Mallas et al^Citation26	2016	1.5	None	None	FA	High
Zhang et al^Citation27	2016	3	None	None	FA	High

Abbreviations: fMRI, functional magnetic resonance imaging; FWHM, full width at half-maximum; NS, not stated; GM, gray matter; WM, white matter; CSF, cerebrospinal fluid; CT, cortical thickness; CF, cortical fold; CSA, cortical surface area; CV, cortical volume; FA, fractional anisotropy; MD, mean diffusivity.

Table 3 Influence of ZNF804A rs1344706 on gray matter (AES-SDM)

Brain region	Peak coordinate					Cluster
	MNI (x, y, z)			SDM-z	P-value	Voxels	Breakdown (voxels)
Positive effects of rs1344706 risk alleles in HC
None
Negative effects of rs1344706 risk alleles in HC
Left superior temporal gyrus	−60	26	10	−2.299	0.00027	252	BA21 (93)
							BA22 (89)
							BA22 (25)
							Corpus callosum (18)
Left median network, cingulum	−4	−22	34	−1.949	0.00076	52	BA23 (29)
Positive effects of rs1344706 risk alleles in SZ
Right inferior frontal gyrus	44	22	−12	2.634	0.00019	248	BA38 (102)
							BA47 (52)
							BA48 (29)
							BA48 (13)
Left superior temporal gyrus	−54	−6	6	2.479	0.00033	83	BA48 (59)
							BA48 (17)
Negative effects of rs1344706 risk alleles in SZ
None

Abbreviations: AES-SDM, Anisotropic Effect-Size Signed Differential Mapping; MNI, Montreal Neurological Institute.

Figure 2 AES-SDM results of the effect of risk allele on gray matter.

Notes: Regions highlighted in red signify increased gray matter in schizophrenia patients carrying risk allele compared with noncarriers. Regions highlighted in blue signify decreased gray matter in healthy individuals carrying risk allele compared with noncarriers.
Abbreviation: AES-SDM, Anisotropic Effect-Size Signed Differential Mapping.

Figure 3 AES-SDM results of the effect of risk allele on white matter.

Note: Regions highlighted in blue signify decreased white matter integrity in healthy individuals carrying risk allele compared with noncarriers.
Abbreviation: AES-SDM, Anisotropic Effect-Size Signed Differential Mapping.

Table 4 Influence of ZNF804A rs1344706 on white matter (AES-SDM)

Brain region	Peak coordinate					Cluster size in voxels
	MNI (x, y, z)			SDM-z	P-value
Positive effects of rs1344706 risk alleles
None
Negative effects of rs1344706 risk alleles
Left median network, cingulum	−16	42	8	−1.100	0.00005	59
Corpus callosum	2	8	24	−1.099	0.00005	52
	20	−42	36	−1.101	0.00001	45

Abbreviations: AES-SDM, Anisotropic Effect-Size Signed Differential Mapping; MNI, Montreal Neurological Institute.

Table 5 Influence of ZNF804A rs1344706 on brain structure (CMA)

Indices	Region	Population	Model	Effect size				Heterogeneity		Egger’s regression intercept		Publication bias
				Z	P-value	D	95% CI	I^2	P-value	T	P-value
Gray matter	Frontal	HC	Random	−2.008	0.045	−0.740	−1.463~–0.018	89.022	0.000	15.644	0.004	Yes
		SZ	Fixed	3.445	0.001	0.778	0.336~1.221	60.166	0.057	1.185	0.358	No
	Temporal	HC	Fixed	−6.099	0.000	−0.958	−1.266~–0.650	17.898	0.301	2.967	0.097	No
		SZ	Random	2.140	0.032	0.302	0.025~0.579	89.678	0.000	0.120	0.916	No
	Parietal	SZ	Fixed	5.346	0.000	1.124	0.712~1.537	0.000	0.923	–	–	–
	Occipital	HC	Fixed	−3.106	0.002	−0.631	−1.030~–0.233	33.581	0.220	–	–	–
		SZ	Fixed	3.605	0.000	0.748	0.342~1.155	54.182	0.140	–	–	–
	Limbic system	HC	Random	−1.485	0.138	−0.900	−2.087~0.288	93.838	0.000	11.921	0.053	No
		SZ	Fixed	4.765	0.000	0.939	0.553~1.325	0.000	0.631	–	–	–
	Basal nuclei	SZ	Fixed	4.689	0.000	0.952	0.554~1.350	0.000	0.869	–	–	–
White matter	All	HC	Random	0.081	0.936	0.018	−0.430~0.467	80.609	0.000	1.325	0.256	No
		SZ	Random	−0.295	0.768	−0.087	−0.667~0.492	79.300	0.008	4.468	0.140	No

Abbreviations: CMA, Comprehensive Meta-Analysis; HC, healty control; SZ, schizophrenia.

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