Copy number variant risk loci for schizophrenia converge on the BDNF pathway

Figures & data

Table 1. CNV pathways created in this study and presentation of schizophrenia risk genes from different sources in those pathways by number and enrichment score (z-score).

WPID	Pathway title	Deleted region^a and reference	Number of protein coding genes in the CNV region	Total number of nodes in the pathway	Number of references in the pathway	Number of inter-actions in the pathway	Dis-I		Dis-M		PGC-all		PGC-filtered
							z-score	^b	z-score	^b	z-score	^b	z-score	^b
WP4905	1q21.1 copy number variation syndrome	146,527,987 − 147,394,444 (Kendall et al. 2017)	7	65	52	24	0.87	1/0	0.03	3/2	1.35	5/0	−0.5	0/0
WP4906	3q29 copy number variation syndrome	195,788,299 − 197,033,296 (Cox and Butler 2015)	20	134	111	48	1.35	0/2	0.66	3/8	−1.48	0/2	−0.69	0/0
WP4932	7q11.23 copy number variation syndrome	72,744,454 − 74,142,513 (Mervis et al. 1993)	23	195	193	61	−0.26	0/1	1.74	1/21	0.19	0/9	1.45	0/2
WP5412	8q11.23 (RB1CC1) copy number variation	53,600,000 – 53,800,000 (Degenhardt et al. 2013)	1	20	11	23	−0.45	0/0	1.19	1/4	0.61	0/2	2.58	0/1
WP4940	15q11.2 copy number variation syndrome	22,805,313 − 23,094,530 (Kendall et al. 2017)	4	29	48	4	−0.34	0/0	0.65	1/1	0.3	0/1	−0.26	0/0
WP4942	15q13.3 copy number variation syndrome	30,500,000 - 32,500,000 (van Bon et al. 1993)	11	51	29	14	1.56	0/1	2.11	4/2	−1.31	0/0	−0.38	0/0
WP3998	Prader-Willi and Angelman syndrome (15q11-q13)	22,805,313 − 28,390,339 (Kirov et al. 2014)	17	191	25	188	0.16	0/1	4.26	5/19	−1.32	0/5	−0.71	0/0
WP4950	16p11.2 distal deletion syndrome	28,823,196 − 29,046,783 (Kendall et al. 2017)	9	52	45	12	0.97	0/1	0.76	1/6	0.28	0/3	−0.48	0/0
WP4949	16p11.2 proximal deletion syndrome	29,592,751 − 30,190,593 (Dell’Edera et al. 2018)	27	212	218	38	−0.98	1/0	0.03	3/2	1.35	5/0	−0.5	0/0
WP4657	22q11.2 copy number variation syndrome	18,912,231 − 21,465,672 (McDonald-McGinn et al. 1993)	45	305	225	95	3.75	0/2	0.66	3/8	−1.48	0/2	−0.69	0/0

^aThese numbers were the query input for BioMart (GRCh37/hg19) to retrieve the list of deleted genes.

^bNumber of schizophrenia risk genes in CNV genetic region/number of risk genes in functionally connected genes

^cz score > 1.96 = The pathway contains significantly more risk genes than expected by chance. Negative scores indicate fewer risk genes in the CNV pathway than expected by chance.

Figure 1. 1q21.1. Copy number variation pathway WP4905. The red arrow indicates the position of the deleted genes on the chromosome. Protein coding gene are black boxes, pseudogenes grey, RNA genes purple, metabolites blue and pathways green. The interactions are annotated interactions carrying the information about the nature of interaction for automated analysis. The small numbers indicate the literature references http://www.wikipathways.org/instance/WP4905.

Table 2. Shared pathways between the different CNVs and their z-scores from schizophrenia risk gene overrepresentation analysis.

ID	Pathway	Dis-I	Dis-M	PGC-all	PGC-filtered
WP5124	Alzheimer’s disease	2.56^a	4.8^a	1.55	5.1^a
WP2059	Alzheimer’s disease and miRNA effects	2.49^a	5.12^a	1.42	5.01^a
WP2380	Brain-Derived Neurotrophic Factor (BDNF) signalling pathway	2.37^a	6.67^a	1.83	0.92
WP4352	Ciliary landscape	−1.67^b	−2.57^b	0.06	−1.27^b
WP306	Focal Adhesion	0.32	1.5	−0.62^b	1.3
WP4659	Gastrin Signalling Pathway	0.46	4.12^a	1.89	0.17
WP4754	IL-18 signalling pathway	−1.33^b	3.09^a	−0.76^b	−0.71^b
WP2034	Leptin signalling pathway	0.04	3.57^a	−0.13^b	0.59
WP5087	Malignant pleural mesothelioma	1.07	2.27^a	−0.94^b	1.01
WP3888	VEGFA-VEGFR2 signalling	−0.64^b	2.4^a3	0.76	−1.25^b

^az-score > 1.96 indicates a significantly overrepresented pathway, indicating more schizophrenia risk genes than expected by chance.

^bz-score < 0 indicates a pathway with fewer schizophrenia risk genes than expected by chance. < -1.96 indicates significantly fewer.

Figure 2. Pathway overlap between the different CNVs. (a) The nine CNV pathways (violet octagons with red borders) (except 15q11.2) share genes (green spheres) with a group of pathways (violet octagons, list in Table 2) that are known to play a role in schizophrenia development. (b) BDNF pathway shares genes (red border) with each of the investigated CNV pathways.

Figure 3. Overlap in schizophrenia risk genes extracted from GWAS studies and DisGeNET database. PGC-all and PGC-filtered (Trubetskoy et al. 2022), Dis-I = intersection/overlap between DisGeNET’s gene-disease and variant-disease associated genes for schizophrenia, Dis-M = merge of DisGeNET’s gene-disease and variant-disease associated genes for schizophrenia.

Kendall KM, Rees E, Escott-Price V, Einon M, Thomas R, Hewitt J, O'Donovan MC, Owen MJ, Walters JTR, Kirov G. 2017. Cognitive performance among carriers of pathogenic copy number variants: analysis of 152,000 UK biobank subjects. Biol Psychiatry. 82(2):103–110. doi: 10.1016/j.biopsych.2016.08.014.

 PubMed Web of Science ®Google Scholar

Cox DM, Butler MG. 2015. A clinical case report and literature review of the 3q29 microdeletion syndrome. Clin Dysmorphol. 24(3):89–94. doi: 10.1097/MCD.0000000000000077.

 PubMed Web of Science ®Google Scholar

Mervis CB, et al. 1993. 7q11.23 duplication syndrome. In: Adam MP, Ardinger HH, Pagon RA editors. Seattle (WA): GeneReviews((R)).

 Google Scholar

Degenhardt F, Priebe L, Meier S, Lennertz L, Streit F, Witt SH, Hofmann A, Becker T, Mössner R, Maier W, et al. 2013. Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets. Transl Psychiatry. 3(11):e326–e326. doi: 10.1038/tp.2013.101.

 PubMedGoogle Scholar

van Bon BWM, et al. 1993. 15q13.3 microdeletion. In: Adam MP, Ardinger HH, Pagon RA editors. Seattle (WA): GeneReviews((R)).

 Google Scholar

Kirov G, Rees E, Walters JT, Escott-Price V, Georgieva L, Richards AL, Chambert KD, Davies G, Legge SE, Moran JL, et al. 2014. The penetrance of copy number variations for schizophrenia and developmental delay. Biol Psychiatry. 75(5):378–385. doi: 10.1016/j.biopsych.2013.07.022.

 PubMed Web of Science ®Google Scholar

Dell’Edera D, Dilucca C, Allegretti A, Simone F, Lupo MG, Liccese C, Davanzo R. 2018. 16p11.2 microdeletion syndrome: a case report. J Med Case Rep. 12(1):90.

 PubMedGoogle Scholar

McDonald-McGinn DM, et al. 1993. 22q11.2. In: Adam MP, Ardinger HH, Pagon RA editors. Seattle (WA): GeneReviews((R)).

 Google Scholar

Trubetskoy V, Pardiñas AF, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli TB, Bryois J, Chen C-Y, Dennison CA, Hall LS, et al. 2022. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 604(7906):502–508. doi: 10.1038/s41586-022-04434-5.

 PubMed Web of Science ®Google Scholar