All genome-wide SNP genotyping for the discovery cohorts was performed using the Illumina HumanHap550 BeadChip at the Center for Applied Genomics at the Children's Hospital of Philadelphia. For family-based cohorts, the association tests for markers in autosomes and pseudoautosomal region of sex chromosomes were performed by PDT, whereas tests for markers in the X chromosome were performed by X-APL. For case-control cohorts, the association tests were performed by PLINK (http://pngu.mgh.harvard.edu/~purcell/plink/). Pathway association analysis was performed by GenGen (http://www.openbioinformatics.org/gengen/), using the genotype data. The whole-genome genotype imputation was performed by MACH (http://www.sph.umich.edu/csg/abecasis/MaCH/) on the autosomal markers, on the basis of phased haplotypes (release 22) for the HapMap CEU population (http://ftp.hapmap.org/phasing/2007-08_rel22/). We removed all markers with MACH Rsq measure of less than 0.3, and zeroed out imputed genotypes with a posterior probability of less than 0.9. The case-control association tests for imputed genotypes were performed by SNPTEST (http://www.stats.ox.ac.uk/~marchini/software/gwas/snptest.html), which can handle genotype imputation uncertainty. CNV calls were generated by PennCNV (http://www. openbioinformatics.org/penncnv/) on genotyping signal intensity data. For CNV validation by multiplex ligation-dependent probe amplification (MLPA), we used the Universal Probe Library
