Extended Data Table 4. Extended results for all PSD genesets.

a. Full PSD geneset association results. For all nine (3 annotation levels by 3 frequency levels), P-values for enrichment of all genesets described and tested in Kirov et al. (2012). In addition to the PSD genes (top five rows), enrichment statistics for presynaptic genes, and neuronal genes clustered on the basis of subcellular location are given. Although the P-values presented are uncorrected, we performed this analysis correcting for all 9×17=153 tests (by considering the distribution of the minimum empirical P-value across tests and sets, as described in the SI). The values in bold are significant (P^corrected < 0.05) after correction for multiple testing. Both ARC and NMDAR network are significant after multiple test correction, for the singleton NS_strict category. (Note: for ARC the disruptive singleton category is, as reported in the primary test, highly significant and withstands correction for multiple testing in that context; in this broader, less focused analysis it yields P^corrected=0.17; the majority of P^corrected values (not shown in Table) are 1.00.) b. PSD and FMRP-target genesets: descriptive statistics and overlap. Overlap between Darnell et al. & Ascano et al. FMRP targets and PSD genes: for example, 57% (16/28) of ARC genes are in the Darnell FMRP list. In contrast, only 7% (2/28) are in the Ascano list. There is a similar trend across the three other major PSD subsets considered here: NMDAR network, PSD-95 and mGluR5 genes. Conversely, 22% of Darnell targets are in the PSD (human core) compared to only 9% of Ascano targets.

a
Set	N genes	Disruptive			Nonsyn. (strict)			Nonsyn. (broad)
		Singletons	MAF< 0.1%	MAF< 0.5%	Singletons	MAF< 0.1%	MAF< 0.5%	Singletons	MAF< 0.1%	MAF< 0.5%
PSD (human core)	685	0.0729	0.1019	0.1083	0.0058	0.1045	0.1285	0.0866	0.5827	0.3743
ARC	28	0.0016	0.0013	0.0014	0.0004	0.0018	0.0047	0.2830	0.4607	0.3542
NMDAR network	61	0.0154	0.0229	0.0225	0.0001	0.0007	0.0005	0.0012	0.1426	0.0420
mGluR5	39	0.1299	0.0861	0.0862	0.0628	0.0837	0.0900	0.0302	0.2192	0.1329
PSD-95	65	0.0015	0.0008	0.0008	0.0027	0.0204	0.0393	0.2992	0.3722	0.1147
Pre-synapse	431	0.0187	0.0983	0.1458	0.2327	0.1811	0.3600	0.1306	0.7597	0.6515
Pre-synaptic active zone	173	0.0518	0.0487	0.0482	0.6162	0.6641	0.7082	0.8439	0.9918	0.9554
Synaptic vesicle	344	0.1030	0.3133	0.4151	0.1439	0.1093	0.2466	0.0375	0.3423	0.2718
Cytoplasm	271	0.5851	0.1793	0.1034	0.8983	0.5351	0.6007	0.1861	0.1084	0.1192
Early Endosomes	17	0.8917	0.7860	0.7826	0.2891	0.2420	0.2139	0.1472	0.4019	0.4123
Endoplasmic Reticulum	97	0.3005	0.1882	0.2612	0.6615	0.2805	0.5036	0.6194	0.5044	0.7878
ER/Golgi-derived vesicles	94	0.4258	0.2678	0.3644	0.3001	0.4977	0.6239	0.3063	0.6944	0.7649
Golgi	31	0.5130	0.5493	0.5481	0.1998	0.0921	0.1338	0.0074	0.1628	0.4178
Mitochondrion	197	0.0141	0.0259	0.0178	0.4351	0.0860	0.0671	0.6999	0.2112	0.6079
Nucleus	167	0.1790	0.3029	0.2900	0.0626	0.1512	0.2728	0.2006	0.3340	0.3196
Plasma membrane	50	0.7940	0.5659	0.5635	0.9416	0.8059	0.8091	0.8944	0.5531	0.3028
Recycling Endosomes/trans-Golgi network	68	0.1502	0.0944	0.1556	0.5349	0.4514	0.5359	0.0902	0.0862	0.1862

b
	N	PSD (human core)		FMRP target (Darnell)		FMRP target (Ascano)
		N	%	N	%	N	%
PSD (human core)	685	-	-	170	25%	80	12%
ARC	28	-	-	16	57%	2	7%
NMDAR network	61	-	-	32	52%	5	8%
mGluR5	39	-	-	25	64%	7	18%
PSD-95	65	-	-	30	46%	4	6%
Pre-synapse	431	213	49%	87	20%	31	7%
Pre-synaptic active zone	173	121	70%	50	29%	10	6%
Synaptic vesicle	344	162	47%	72	21%	27	8%
Cytoplasm	271	77	28%	16	6%	23	8%
Early Endosomes	17	6	35%	2	12%	1	6%
Endoplasmic Reticulum	97	13	13%	5	5%	4	4%
ER/Golgi-derived vesicles	94	24	26%	7	7%	4	4%
Golgi	31	2	6%	2	6%	4	13%
Mitochondrion	197	57	29%	6	3%	12	6%
Nucleus	167	19	11%	7	4%	19	11%
Plasma membrane	50	16	32%	6	12%	5	10%
Recycling Endosomes/trans-Golgi network	68	19	28%	3	4%	7	10%
Total	1509	685	45%	170	11%	80	5%