SUPPLEMENTARY INFORMATION

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Tyler Powell
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1 SUPPLEMENTRY INFORMTION Supplementary Figure 1. Q-Q plot of RE/NIMH autism family TDT results. The quantile-quantile plot of the expected and observed P-values is shown. The blue circles represent the observed data, the grey line is the expectation under the null hypothesis of no association, and the red curves are the boundaries of the 95% confidence interval. Data included are those passing our final QC. 1

SUPPLEMENTRY INFORMTION 6 5 4 -log 10 P 3 2 1 chr 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1516 16 18 20 22 17 19 21 X Supplementary Figure 2. enome-wide ssociation Results.

2 SUPPLEMENTRY INFORMTION log 10 P chr X Supplementary Figure 2. enome-wide ssociation Results. The genome-wide TDT results are shown, with each chromosome represented by a different color. The blue line indicates P < 10-4, the significance at which we attempted to replicate results, and the red line indicates P < Data included are those passing our final QC. 2

3 SUPPLEMENTRY INFORMTION Supplementary Figure 3. Top TDT result. The 5p15 region is shown. The light blue lines represent recombination frequency, green lines represent the annotated genes, observed data are shown as diamonds, and imputed data are shown as circles. The most significant SNP is shown in blue with other SNPs in LD shaded in red, with darker colors indicating stronger LD. n imputed SNP (rs ) showed stronger association than the genotyped SNP in the same region. The green symbol represents the results of meta-analysis. 3

4 SUPPLEMENTRY INFORMTION Supplementary Figure 4. enotype plots of RE ffymetrix 5.0 data for rs plate plate rs enotype data is shown for each of the well plates of RE samples genotyped at plate plate plate 5 the Broad Institute, as well as the combined data (bottom right). Intensity data are plotted, with genotype calls indicated by color: blue, yellow, green plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate plate all 4

5 SUPPLEMENTRY INFORMTION Supplementary Figure 4. enotype plots of RE ffymetrix 5.0 data for rs enotype data is shown for each of the well plates of RE samples genotyped at the Broad Institute, as well as the combined data (bottom right). Intensity data are plotted, with genotype calls indicated by color: blue, yellow, green. Supplementary Table 1. Families used for genetic analysis. See file s2 pp 1-80 RE and NIMH families included in the genome-wide analysis. Each family and individual ID is shown, along with affection status used for analysis. Supplementary Table 2. Linkage analysis. See file s2 pp Linkage analysis results (see Methods) are given with LOD scores for all families and for families with both parents genotyped. 5

6 SUPPLEMENTRY INFORMTION Supplementary Table 3. Top TDT results. scan replication meta-analysis chr position SNP proxy_ld T U OR P P (w case-control) T U OR P (1sided) Pmeta Pproxy rs E rs E rs rs r 2 = 0.48, rs rs E N rs r 2 = 0.67, rs N rs E N rs E N rs E N rs rs E rs E E rs rs rs r 2 =0.71, rs N rs E E rs E N rs E rs E rs rs r 2 =0.74, rs N N N N N rs E rs E rs E rs r 2 =1,rs N N N N N rs E rs E rs N rs E rs r 2 =0.6, rs N N N N N rs E N rs E rs E E rs E N rs E N rs E rs E N rs rs E N rs E rs E N rs E E rs N rs E N XY rs E Top results from the RE-NIMH TDT (P < 10-4 ) are shown, with replication data, where it exists. For Sequenom genotyping that used a proxy SNP, that SNP and its LD (r 2 ) with the SNP of interest is shown. Transmitted (T) and untransmitted (U) counts and odds ratios (OR) for the minor allele are shown for each SNP. Replication results are shown for additional autism family data using ffymetrix and Sequenom genotyping technology. The meta-analysis P-value is shown, and the P-value for meta-analysis where proxy SNP data was included. Bold font, P < 10-5 TDT/case-control analysis, P < 0.05 replication, P < 2.5 x 10-7 meta-analysis. 6

7 SUPPLEMENTRY INFORMTION Supplementary Table 4. Imputation analysis in autism. imputation for RE/NIMH samples direct genotyping CHR SNP BP INFO T U OR P all_or all_p 1 rs E rs E-06 5 rs E E-06 5 rs E E-05 5 rs E-06 5 rs E-06 5 rs E-07 5 rs E-06 6 rs E-06 6 rs E rs E-06 9 rs E rs E rs E The top results from imputation analysis (P < 10-5 ) are shown for autosomes in the complete sample (RE and NIMH multiplex families). The odds ratio and P-value for direct genotyping are shown, where available. 7

8 SUPPLEMENTRY INFORMTION Supplementary Table 5. Set-based Tests of Candidate enes and Regions in utism TDT analysis of microdeletion and microduplication regions implicated in autism Region # SNPs Best TDT SNP & P value (OR) Empirical P region set 15q rs (2.1) 16p ns Potocki-Lupski 248 rs syndrome (0.43) Prader-Willi & ngelman 863 rs syndromes (0.64) Velo-Cardio-Facial 287 SNP_ syndrome (0.56) Williams syndrome 73 rs (0.56) (S1) TDT analysis of Mendelian disease genes implicated in autism Disease (gene) # SNPs Best TDT SNP & P Empirical P region set value (OR) Joubert syndrome 8 ns (HI1) Timothy syndrome 103 rs (CCN1C) (0.89) Smith-Lemli-Opitz 3 ns syndrome (DHCR7) Fragile X syndrome 1 ns (FMR1) Rett syndrome 5 rs (S5) ns (MECP2) (0.79) Neurofibromatosis type I 11 ns (NF1) Cowden disease 3 ns (PTEN) Tuberous Sclerosis type 7 rs I (TSC1) (1.3) Tuberous Sclerosis type II (TSC2) 2 rs (0.77) (S1) ns 8

9 SUPPLEMENTRY INFORMTION TDT analysis of genes with rare mutations implicated in autism ene # SNPs Best TDT SNP & P value (OR) Empirical P region set NRXN1 182 rs (0.70) NLN4X 40 rs (0.82) SHNK3 2 ns TDT analysis of candidate genes implicated by association studies in autism ene # SNPs Best TDT SNP & P value (OR) Empirical P region set VPR1 3 ns CNTNP2 355 rs (0.68) DISC1 69 rs (1.2) RIK2 59 rs (0.87) EN2 2 ns BRB3 27 rs (1.3) ITB3 14 ns MET 14 rs (0.87) OXTR 7 ns RELN 87 rs (0.85) SLC ns SLC64 3 ns Supplementary Table 5. Set-based tests of candidate genes and regions in autism. Four sets of regions and genes of prior interest in autism were examined: microdeletion and microduplications, Mendelian disease genes, genes with rare mutations, and genes with common variant association reported in autism 1. For each, the number of SNPs in the region (or gene +/- 2kb), the best single SNP TDT result and its odds ratio (OR), the best empirical P-value with number of SNPs used, the gene-based corrected test, and setbased corrected test are shown. 9

10 SUPPLEMENTRY INFORMTION Supplementary Table 6. ssociation results in linkage regions. SNPs in linkage regions P < 0.01 chr snp bp a1 a2 T 6q27 rs T C p13 rs p13 rs C T p13 rs C T 728 haplotypes in linkage regions P < chr snps haplo bp_first bp_last T 6q27 rs rs rs rs rs CC q27 rs rs rs rs rs TCCC q27 rs rs rs rs rs CTTTC q27 rs rs rs rs rs TTTC p13 rs rs rs rs rs CCTC p13 rs rs rs rs rs CCCT Single SNP (P < 10-2 ) and 5-SNP haplotype association results (P < 10-3 ) in the significant and suggestive linkage regions are shown. 10

Supplementary Figure 1: Attenuation of association signals after conditioning for the lead SNP. a) attenuation of association signal at the 9p22.

Supplementary Figure 1: Attenuation of association signals after conditioning for the lead SNP. a) attenuation of association signal at the 9p22.32 PCOS locus after conditioning for the lead SNP rs10993397;