☰ Schizophrenia in 22q11.2DS

22q11.2 deletion syndrome (22q11.2DS) is a severe developmental disorder, caused predominantly by a 3-Mb genomic deletion (in ~85% of cases). About one in four individuals with 22q11.2DS develops schizophrenia (SCZ), usually in late adolescence or early adulthood. To uncover genetic variation that contributes to the high prevalence of SCZ in 22q11.2DS, the International 22q11.2DS Brain and Behavior Consortium (IBBC) assembled and whole-genome sequenced (WGS) a cohort of 519 22q11.2DS patients with and without SCZ. In this study, we describe an analytic framework that incorporates Integrated Gene Signal Processing (IGSP) to uncover modifier rare coding variants associated with SCZ in 22q11.2DS and elucidate the functional connection between modifier genes and 22q11.2 deletion in brain development.

Citation

Rare coding variants as risk modifiers of the 22q11.2 deletion implicate postnatal cortical development in syndromic schizophrenia. Lin JR, Zhao Y, Jabalameli MR, Nguyen N, Mitra J, Swillen A, Vorstman JAS, Chow EWC, van den Bree M, Emanuel BS, Vermeesch JR, Owen MJ, Williams NM, Bassett AS, McDonald-McGinn DM, Gur RE, Bearden CE, Morrow BE, Lachman HM, Zhang ZD (2023) Mol Psychiatry.  JOURNAL   PUBMED   REPRINT   WEBSITE 

☰ Idiopathic schizophrenia

We developed a general computational framework for post-GWAS analysis to predict complex disease genes. We identified 132 schizophrenia risk genes in 76 risk regions spanning 120 schizophrenia-associated common variants, 78 of which have not been recognized as schizophrenia disease genes by previous GWAS. Even more significantly, 29 of them are distal to the risk regions, likely under regulation of transcriptional regulatory elements therein contained.

Citation

Integrated post-GWAS analysis shed new light on the disease mechanisms of schizophrenia. Lin JR, Cai Y, Zhang Q, Zhang W, Nogales-Cadenas R, Zhang ZD (2016) Genetics 204(4):1587-1600.  JOURNAL   PUBMED   REPRINT 

Schizophrenia risk genes

SZ variant	Chr	Position *	GWAS reference	Predicted risk genes (& scores)
rs4648845	1	2387101	Ripke S et al
rs2252865	1	8422676	Ripke S et al
chr1_8424984_D	1	8424984	Ripke S et al
rs4846033	1	11788564	Sullivan PF et al
rs1009080	1	30431560	Ripke S et al
rs1498232	1	30433951	Ripke S et al
rs589249	1	37162352	Aberg KA et al	GRIK3 (200.3)
rs11210892	1	44100084	Ripke S et al	TIE1 (167.5)
rs12129573	1	73768366	Ripke S et al
rs10789369	1	73824909	Ripke S et al
rs12071951	1	97113915	Bergen SE et al
rs7544736	1	97164343	Purcell SM et al
rs76869799	1	97834525	Ripke S et al
rs1702294	1	98501984	Ripke S et al
rs1625579	1	98502934	Ripke S et al
rs1198588	1	98552832	Bergen SE et al
rs140505938	1	150031490	Ripke S et al	MCL1 (182.2)
rs10489202	1	167903079	Shi Y et al
rs6670165	1	177280121	Ripke S et al
rs12140439	1	177722907	Aberg KA et al
rs10911902	1	186632317	Sullivan PF et al	PTGS2 (1364.2), TPR (185.0), PDC (111.9)
rs7523273	1	207977083	Ripke S et al	CD34 (346.3), CD46 (80.6)
rs7527939	1	210536025	Betcheva ET et al
rs1538774	1	243544827	Ripke S et al
rs77149735	1	243555105	Ripke S et al
rs10803138	1	243555219	Ripke S et al
rs6703335	1	243608967	Ripke S et al
rs14403	1	243663893	Ripke S et al
chr1_243881945_I	1	243881945	Ripke S et al
rs10429924	1	244390564	Levinson DF et al
rs10924245	1	245733608	Fanous AH et al
rs2373000	2	37592628	Ripke S et al
rs4381823	2	48047335	Aberg KA et al	MSH6 (152.5)
rs11682175	2	57987593	Ripke S et al
rs75575209	2	58138192	Ripke S et al
rs2312147	2	58222928	Stefansson H et al
rs3768644	2	72361505	Ripke S et al
rs1170612	2	124983056	Levinson DF et al
rs12991836	2	145141541	Ripke S et al	ZEB2 (140.3)
chr2_146436222_I	2	146436222	Ripke S et al
chr2_149429178_D	2	149429178	Ripke S et al
rs2909457	2	162845855	Ripke S et al	DPP4 (933.8), GCA (88.6)
rs11693094	2	185601420	Ripke S et al
rs1344706	2	185778428	O'Donovan MC et al
rs4380187	2	185811940	Ripke S et al
rs59979824	2	193848340	Ripke S et al
rs17662626	2	193984621	Ripke S et al
rs6434928	2	198304577	Ripke S et al	HSPD1 (154.5)
rs6704641	2	200164252	Ripke S et al
rs2949006	2	200715388	Ripke S et al
chr2_200825237_I	2	200825237	Ripke S et al
rs11685299	2	225391296	Ripke S et al
rs6704768	2	233592501	Ripke S et al
rs778371	2	233743109	Ripke S et al
rs13025591	2	236795343	Ripke S et al
rs17194490	3	2547786	Ripke S et al	CNTN4 (184.2)
rs4330281	3	17859366	Ripke S et al
rs75968099	3	36858583	Ripke S et al
rs4624519	3	36862980	Ripke S et al
rs6550435	3	36864489	Ripke S et al
rs4687552	3	52838402	Ripke S et al	PRKCD (439.5), ITIH4 (140.8), NISCH (138.6), GNL3 (89.9)
rs2535627	3	52845105	Ripke S et al	PRKCD (439.5), ITIH4 (140.8), NISCH (138.6), GNL3 (89.9)
rs2239547	3	52855229	Ripke S et al	PRKCD (439.5), ITIH4 (140.8), NISCH (138.6), GNL3 (89.9)
rs11130874	3	62064769	Ripke S et al
rs832187	3	63833050	Ripke S et al
rs17203055	3	119084331	Aberg KA et al
rs7432375	3	136288405	Ripke S et al
rs1351267	3	151763701	Fanous AH et al
rs6782299	3	180550702	Purcell SM et al
rs1879248	3	180551214	Ripke S et al
chr3_180594593_I	3	180594593	Ripke S et al
rs9841616	3	181167585	Ripke S et al	SOX2 (198.1)
rs959770	4	2395297	Fanous AH et al	ADD1 (129.7)
rs215411	4	23423603	Ripke S et al	PPARGC1A (250.8)
rs35518360	4	103146890	Ripke S et al
rs11098403	4	118646907	Lencz T et al
rs10520163	4	170626552	Ripke S et al	CLCN3 (131.4)
rs1106568	4	176861301	Ripke S et al
rs2726807	4	183137398	Levinson DF et al	TENM3 (98.4)
rs1501357	5	45364875	Ripke S et al	HCN1 (146.9)
rs10052004	5	56666500	Fanous AH et al
rs171748	5	60499131	Ripke S et al
rs4391122	5	60598543	Ripke S et al
rs7709645	5	60731458	Bergen SE et al
rs17206232	5	64433400	Fanous AH et al
rs16867576	5	88746331	Ripke S et al	MEF2C (170.5)
rs6878284	5	101769726	Ripke S et al	PAM (188.1)
rs1502844	5	101859317	Stefansson H et al	PAM (188.1)
rs4388249	5	109036066	Ripke S et al	PJA2 (145.9)
rs10043984	5	137712121	Ripke S et al	EGR1 (1060.1), CTNNA1 (106.0)
rs3849046	5	137851192	Ripke S et al	EGR1 (1060.1), CTNNA1 (106.0)
chr5_140143664_I	5	140143664	Ripke S et al	CD14 (1051.8), HBEGF (189.8), IK (134.5)
rs79212538	5	151993104	Ripke S et al	GRIA1 (344.5), NMUR2 (167.7)
rs111294930	5	152177121	Ripke S et al	GRIA1 (344.5), NMUR2 (167.7)
rs2910032	5	152540354	Ripke S et al	GRIA1 (344.5), NMUR2 (167.7)
rs2973155	5	152608619	Ripke S et al	GRIA1 (344.5), NMUR2 (167.7)
rs17504622	5	152654479	Ripke S et al	GRIA1 (344.5), NMUR2 (167.7)
rs12522290	5	152797656	Ripke S et al	GRIA1 (344.5), NMUR2 (167.7)
rs11740474	5	153680747	Ripke S et al
rs12210050	6	475489	Levinson DF et al
rs13194053	6	27143883	Shi J et al
rs6932590	6	27248931	Stefansson H et al
rs16897515	6	27278020	Aberg KA et al
rs17693963	6	27710165	Bergen SE et al
rs1635	6	28227604	Yue WH et al
rs115329265	6	28712247	Ripke S et al
rs2523722	6	30165273	Donnelly P et al
rs2021722	6	30174131	Ripke S et al
rs1046089	6	31602967	Aberg KA et al	CYP21A2 (299.8), AIF1 (185.2), APOM (147.1), AGER (105.8), CLIC1 (80.6)
rs3132935	6	32171075	Aberg KA et al	CYP21A2 (299.8), TAP1 (173.0), NOTCH4 (151.4), TNXB (137.0), HLA-DQB1 (114.6), HLA-DRB1 (107.4), AGER (105.8), HLA-DRA (86.5)
rs3131296	6	32172993	Stefansson H et al	CYP21A2 (299.8), TAP1 (173.0), NOTCH4 (151.4), TNXB (137.0), HLA-DQB1 (114.6), HLA-DRB1 (107.4), AGER (105.8), HLA-DRA (86.5)
rs114002140	6	32431962	Ripke S et al	CYP21A2 (299.8), TAP1 (173.0), NOTCH4 (151.4), TNXB (137.0), HLA-DQB1 (114.6), HLA-DRB1 (107.4), AGER (105.8), HLA-DRA (86.5)
rs4530903	6	32581889	Fanous AH et al	CYP21A2 (299.8), TAP1 (173.0), NOTCH4 (151.4), TNXB (137.0), HLA-DQB1 (114.6), HLA-DRB1 (107.4), AGER (105.8), HLA-DRA (86.5)
rs9272219	6	32602269	Shi J et al	CYP21A2 (299.8), TAP1 (173.0), NOTCH4 (151.4), TNXB (137.0), HLA-DQB1 (114.6), HLA-DRB1 (107.4), AGER (105.8), HLA-DRA (86.5)
rs16869652	6	33851173	Levinson DF et al
rs1339227	6	73155701	Ripke S et al	RIMS1 (357.2)
chr6_84280274_D	6	84280274	Ripke S et al
rs117074560	6	96459651	Ripke S et al
rs12666575	7	2004421	Bergen SE et al
rs6461049	7	2017445	Ripke S et al
chr7_2025096_I	7	2025096	Ripke S et al
chr7_24747494_D	7	24747494	Ripke S et al
rs12699131	7	71751316	Ripke S et al
rs12704290	7	86427626	Ripke S et al	GRM3 (378.2)
rs7341475	7	103404815	Shifman S et al	RELN (562.0)
rs6466055	7	104929064	Ripke S et al
rs211829	7	110048893	Ripke S et al	IMMP2L (153.6)
rs13240464	7	110898915	Ripke S et al	IMMP2L (153.6), DOCK4 (90.2)
rs7801375	7	131567263	Ripke S et al
rs3735025	7	137074844	Ripke S et al	PTN (174.6)
rs10503253	8	4180844	Ripke S et al
rs10503256	8	4214179	Bergen SE et al
rs7017212	8	10022938	Ma X et al
rs73229090	8	27442127	Ripke S et al	CLU (348.9), EPHX2 (192.7)
rs16887244	8	38031345	Shi Y et al	FGFR1 (926.8), STAR (822.7)
rs6984242	8	60700469	Ripke S et al
rs7819570	8	89588626	Ripke S et al	MMP16 (303.7)
rs11995572	8	89592083	Ripke S et al	MMP16 (303.7)
rs7004633	8	89760311	Ripke S et al	MMP16 (303.7)
rs36068923	8	111485761	Ripke S et al	KCNV1 (88.8)
rs4129585	8	143312933	Ripke S et al
rs7045881	9	26935996	Athanasiu L et al
rs489332	9	78028346	Fanous AH et al
rs11139497	9	84739941	Ripke S et al
rs1572299	9	121346417	Stefansson H et al
rs17691888	10	18734528	Ripke S et al	CACNB2 (101.7)
rs7893279	10	18745105	Ripke S et al	CACNB2 (101.7)
rs3847375	10	21567565	Levinson DF et al
rs1412115	10	34088053	Alkelai A et al	PARD3 (100.2)
rs10900020	10	44827197	Fanous AH et al	CXCL12 (1114.3)
rs10761482	10	62085337	Athanasiu L et al	ANK3 (135.1)
rs16915157	10	62346638	Ripke S et al	ANK3 (135.1)
rs7907645	10	104423800	Ripke S et al	CYP17A1 (416.5), NEURL (127.1)
rs11191419	10	104612335	Ripke S et al	CYP17A1 (416.5), NEURL (127.1)
rs7085104	10	104628873	Ripke S et al	CYP17A1 (416.5), NEURL (127.1)
rs7897654	10	104662458	Aberg KA et al	CYP17A1 (416.5), NEURL (127.1)
rs55833108	10	104741583	Ripke S et al	CYP17A1 (416.5), NEURL (127.1)
rs7914558	10	104775908	Ripke S et al	CYP17A1 (416.5), NEURL (127.1)
rs11191580	10	104906211	Ripke S et al	CYP17A1 (416.5), NEURL (127.1)
chr10_104957618_I	10	104957618	Ripke S et al	CYP17A1 (416.5), NEURL (127.1)
rs4757144	11	13331226	Borglum AD et al	ARNTL (359.6)
rs4356203	11	17160148	Ripke S et al	PIK3C2A (213.8), NUCB2 (111.3)
rs11027857	11	24403620	Ripke S et al
rs1602565	11	29162136	O'Donovan MC et al
rs11038167	11	44843134	Yue WH et al
chr11_46350213_D	11	46350213	Ripke S et al	MDK (197.0), CHRM4 (160.6), DGKZ (148.9)
rs9420	11	57510294	Ripke S et al	SERPING1 (137.5), CTNND1 (105.5)
rs12421382	11	109378071	Ripke S et al
rs2514218	11	113392994	Ripke S et al	DRD2 (1420.9), HTR3B (125.1)
rs77502336	11	123394636	Ripke S et al
rs12807809	11	124606285	Stefansson H et al	NRGN (90.1)
rs55661361	11	124613957	Ripke S et al	NRGN (90.1)
rs7930295	11	125313599	Aberg KA et al	EI24 (220.3), CHEK1 (136.9)
rs11220082	11	125323965	Bergen SE et al	EI24 (220.3), CHEK1 (136.9)
rs548181	11	125461709	Ripke S et al	EI24 (220.3), CHEK1 (136.9)
rs10791097	11	130718630	Ripke S et al
rs7940866	11	130817579	Ripke S et al
rs10894294	11	130830748	Ripke S et al
rs75059851	11	133822569	Ripke S et al
rs2007044	12	2344960	Ripke S et al	CACNA1C (597.1)
rs1006737	12	2345295	Ripke S et al	CACNA1C (597.1)
rs4765905	12	2349584	Ripke S et al	CACNA1C (597.1)
rs2239063	12	2511831	Ripke S et al	CACNA1C (597.1)
rs16934812	12	29872318	Levinson DF et al
rs679087	12	29917265	Ripke S et al
rs324017	12	57487814	Ripke S et al	LRP1 (692.5), STAT6 (144.1), MYO1A (138.6), TAC3 (113.4)
rs12826178	12	57622371	Ripke S et al	LRP1 (692.5), STAT6 (144.1), MYO1A (138.6), TAC3 (113.4)
rs12426725	12	81843128	Levinson DF et al
rs4240748	12	92246786	Ripke S et al	BTG1 (100.8)
rs10860964	12	103596455	Ripke S et al
rs4766428	12	110723245	Ripke S et al	ATP2A2 (215.8)
rs1920592	12	114705586	Fanous AH et al
rs11064768	12	119818509	Kirov G et al
rs2851447	12	123665113	Ripke S et al
rs11532322	12	123731423	Ripke S et al
rs9512730	13	28077144	Sullivan PF et al
rs2323266	13	61965303	Fanous AH et al
rs2068012	14	30190316	Ripke S et al	PRKD1 (1104.4)
rs2332700	14	72417326	Ripke S et al	RGS6 (99.8)
rs2693698	14	99719219	Ripke S et al
rs12887734	14	104046834	Ripke S et al
rs56205728	15	40567237	Ripke S et al	RAD51 (481.9), PLCB2 (209.8), PAK6 (149.7)
rs1869901	15	40595627	Ripke S et al	RAD51 (481.9), PLCB2 (209.8), PAK6 (149.7)
rs7172342	15	61336442	Fanous AH et al
rs4775413	15	61840103	Ripke S et al
rs12903146	15	61854663	Ripke S et al
rs12592967	15	61870943	Bergen SE et al
rs12148337	15	70589272	Ripke S et al
rs190065944	15	78859610	Ripke S et al	CHRNA3 (323.5), CHRNB4 (269.3), CHRNA5 (161.0)
rs8042374	15	78908032	Ripke S et al	CHRNA3 (323.5), CHRNB4 (269.3), CHRNA5 (161.0)
rs950169	15	84706461	Ripke S et al
rs16977195	15	86984240	Sullivan PF et al
rs4702	15	91426560	Ripke S et al	FURIN (326.3), FES (286.1), SV2B (107.8)
rs9922678	16	9946319	Ripke S et al	GRIN2A (1385.0)
rs12922317	16	12077632	Borglum AD et al
rs7192086	16	13061611	O'Donovan MC et al
rs7405404	16	13749859	Ripke S et al	ERCC4 (147.7)
rs151222	16	20674492	Sullivan PF et al
rs433598	16	20680206	Athanasiu L et al
rs12691307	16	29939877	Ripke S et al	MAPK3 (915.7), DOC2A (249.6), TAOK2 (93.7)
rs17290922	16	57024317	Fanous AH et al	CCL22 (159.4), CETP (99.7)
rs12325245	16	58681393	Ripke S et al
rs8044995	16	68189340	Ripke S et al	PLA2G15 (854.0), LCAT (148.3), SLC12A4 (100.3)
rs8057927	16	82692812	Borglum AD et al	CDH13 (231.7)
rs4523957	17	2208899	Ripke S et al	SRR (104.4)
rs8082590	17	17958402	Ripke S et al	SREBF1 (388.5), FLII (87.9), MYO15A (84.0)
rs1455244	18	11494199	Fanous AH et al	GNAL (612.4)
rs2048485	18	42090667	Levinson DF et al
chr18_52749216_D	18	52749216	Ripke S et al	TCF4 (522.1)
rs12966547	18	52752017	Ripke S et al	TCF4 (522.1)
rs4801131	18	52752700	Ripke S et al	TCF4 (522.1)
rs1261117	18	52949657	Aberg KA et al	TCF4 (522.1)
rs17594526	18	53058238	Purcell SM et al	TCF4 (522.1)
rs78322266	18	53063676	Ripke S et al	TCF4 (522.1)
rs9960767	18	53155002	Stefansson H et al	TCF4 (522.1)
rs17512836	18	53194961	Ripke S et al	TCF4 (522.1)
rs9636107	18	53200117	Ripke S et al	TCF4 (522.1)
rs72934570	18	53533189	Ripke S et al	TCF4 (522.1)
rs715170	18	53795514	Ripke S et al	TCF4 (522.1)
rs4798896	18	75912922	Fanous AH et al
rs7233060	18	77392379	Fanous AH et al
rs2905424	19	19473445	Ripke S et al
rs2905426	19	19478022	Ripke S et al
rs2053079	19	30987423	Ripke S et al
rs12611334	19	40229409	Aberg KA et al
rs4803480	19	42066279	Alkelai A et al
rs56873913	19	50091199	Ripke S et al	RRAS (127.3), PRMT1 (116.7)
rs6065094	20	37453194	Ripke S et al
rs7267348	20	48131036	Ripke S et al	PTGIS (155.5)
rs11699237	20	55683996	Fanous AH et al	BMP7 (210.8)
rs9611198	22	39955873	Donnelly P et al et al
chr22_39987017_D	22	39987017	Ripke S et al
rs9607782	22	41587556	Ripke S et al	EP300 (210.8), RANGAP1 (91.0)
rs1023500	22	42340844	Ripke S et al	CYP2D6 (275.3), SREBF2 (105.2)
rs6002655	22	42603814	Ripke S et al	CYP2D6 (275.3), SREBF2 (105.2)
rs138880	22	50218611	Aberg KA et al	MAPK11 (97.4), MLC1 (80.7)
rs12845396	X	6029533	Ripke S et al	NLGN4X (554.6)
rs1378559	X	21380266	Ripke S et al	CNKSR2 (83.6)
rs5937157	X	68377126	Ripke S et al
rs2159767	X	147381021	Sullivan PF et al	FMR1 (85.7)
rs2269372	X	153207545	Wong EH et al	OPN1LW (359.6), MECP2 (310.3), IRAK1 (301.1), FLNA (246.1), AVPR2 (229.9), HCFC1 (122.0), L1CAM (103.6), ARHGAP4 (89.0)

 * All positions are based on the GRCh37/hg19 human genome assembly.