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Discovery of the First Genome-Wide Significant Risk Loci for ADHD

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Discovery of the First Genome-Wide Significant Risk Loci for ADHD Supplementary Information Discovery of the first genome-wide significant risk loci for ADHD Table of Contents Supplementary Methods and Results .......................................................................................... 4 Detailed description of individual Samples ........................................................................................... 4 iPSYCH, Denmark ............................................................................................................................................. 4 Samples from the Psychiatric Genomics Consortium (PGC) ................................................................................ 6 Parent-offspring trio samples .............................................................................................................................. 6 CHOP, USA ....................................................................................................................................................... 6 IMAGE-I, Europe .............................................................................................................................................. 6 PUWMa, USA ................................................................................................................................................... 7 Toronto, Canada .............................................................................................................................................. 8 Case-control samples ........................................................................................................................................... 9 Barcelona, Spain .............................................................................................................................................. 9 Beijing, China ................................................................................................................................................... 9 Bergen, Norway ............................................................................................................................................. 10 Cardiff, UK ..................................................................................................................................................... 10 Germany ........................................................................................................................................................ 11 IMAGE-II, Europe & USA ................................................................................................................................ 12 Yale-Penn, USA .............................................................................................................................................. 13 Replication samples ........................................................................................................................................... 14 23andMe, self-reported ADHD diagnoses ..................................................................................................... 14 EAGLE, ADHD symptom scores ..................................................................................................................... 15 Bioinformatic pipeline for quality control and association analyses .................................................... 17 Pre-imputation quality control .......................................................................................................................... 17 Genotype imputation ......................................................................................................................................... 17 Relatedness and population stratification ......................................................................................................... 18 GWAS and meta-analysis .................................................................................................................... 19 Defining independent genome-wide significant loci ........................................................................... 21 Evaluating putative secondary signals ................................................................................................ 21 Correlation of secondary signals with their respective lead index variants ....................................................... 21 Conditional association analysis ........................................................................................................................ 22 Bayesian credible set analysis ............................................................................................................ 22 Credible set estimation method ........................................................................................................................ 23 Variants considered for credible set analysis ..................................................................................................... 24 Credible set results in PGC and iPSYCH data ...................................................................................................... 25 Functional annotation of variants in credible set .............................................................................................. 25 Gene-based association analysis ........................................................................................................ 27 Exome-wide association of single genes with ADHD ......................................................................................... 27 Gene-wise association of candidate genes for ADHD ........................................................................................ 28 Gene-set analyses .............................................................................................................................. 28 1 Hypothesis free gene set analyses ..................................................................................................................... 28 FOXP2 downstream target gene set analysis ..................................................................................................... 29 Highly constrained gene set analysis ................................................................................................................. 30 LD Score intercept evaluation ............................................................................................................. 30 Genetic correlations between PGC and iPSYCH ADHD samples ........................................................... 31 Genetic correlation between PGC case-control and trio samples ........................................................ 31 Polygenic risk scores for ADHD ........................................................................................................... 32 Polygenic risk score prediction in iPSYCH samples ............................................................................................ 33 Polygenic risk score prediction in PGC samples ................................................................................................. 34 Leave-one-out analysis across cohorts .............................................................................................................. 35 SNP heritability .................................................................................................................................. 35 Partitioning heritability by functional annotation and cell type .......................................................... 36 Genetic correlations of ADHD with other traits .................................................................................. 37 Replication analysis in 23andMe and EAGLE cohorts .......................................................................... 38 Sign test ............................................................................................................................................................. 38 Replication meta-analyses and heterogeneity tests .......................................................................................... 39 Results for replication in 23andMe .................................................................................................................... 40 Results for replication in EAGLE ......................................................................................................................... 41 Results for ADHD+23andMe+EAGLE meta-analysis ........................................................................................... 42 Method for meta-analysis of continuous and dichotomous ADHD measures ...................................... 43 Basic genetic model for latent-scale phenotypes .............................................................................................. 44 Defining independent genetic factors ................................................................................................................ 45 Effects of individual variants .............................................................................................................................. 46 GWAS test statistics for ßj .................................................................................................................................. 48 Test of ßij in GWAS of dichotomous Y1 ............................................................................................................... 50 Test of ß1j in GWAS of continuous Y2 ................................................................................................................
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