I computed LD ratingramss having fun with LDSC v1

To help you estimate said difference from PRS into the phenotype, set up a baseline linear matchmaking as well as only sex and you will tall Pcs because the parameters are modelled very first:

0.0 in 1 centiMorgan windows around 13,307,412 non-singleton variants genotyped in 379 European individuals (CEU, FIN, GBR, IBS and TSI populations) in the phase 1 integrated release of the 1,000 Genomes Project 35 . For regression weights 13 , we restricted LD score calculation to SNPs included in both the GWAS sumap phase 3; for r_g estimation in pairs of traits this was the intersection of SNPs for http://www.datingranking.net/local-hookup/london/ both traits and HapMap. Because population structure and confounding were highly controlled in the ALS summary statistics by the use of mixed linear model association tests, we constrained the LD score regression intercept to 1 for h_S 2 estimation in ALS, and we also estimated h_S 2 with a free intercept. For h_S 2 estimation in all other traits and for r_g estimation the intercept was a free parameter. We also estimated r_g using ALS meta-analysis results 7 with free and constrained intercepts and with permuted data conserving population structure. Briefly, principal component analysis was carried out for each stratum using smartpca 36 and the three-dimensional space defined by principal components 1–3 was equally subdivided into 1,000 cubes. Within each cube, case–control labels were randomly swapped and association statistics were re-calculated for the entire stratum using logistic regression. Study-level P-values were then calculated using inverse variance weighted fixed effect meta-analysis implemented in METAL 7,12 . h_S 2 was estimated for these meta-analysed permuted data using LD score regression (Supplementary Table 1).

Polygenic risk score data

We calculated PRS for 10,032 cases and 16,627 healthy controls in the ALS dataset (duplicate and suspected or confirmed related samples with the schizophrenia dataset removed), based on schizophrenia-associated alleles and effect sizes reported in the GWAS summary statistics for 6,843,674 SNPs included in both studies and in the phase 1 integrated release of the 1,000 Genomes Project 35 (imputation INFO score <0.3; minor allele frequency <0.01; A/T and G/C SNPs removed). SNPs were clumped in two rounds (physical distance threshold of 250 kb and a LD threshold (R 2 ) of>0.5 in the first round and a distance of 5,000 kb and LD threshold of >0.2 in the second round) using PLINK v1.90b3y, removing high-LD regions (Supplementary Table 4), resulting in a final set of 496,548 SNPs for PRS calculations. Odds ratios for autosomal SNPs reported in the schizophrenia summary statistics were log-converted to beta values and PRS were calculated using PLINK’s score function for twelve schizophrenia GWAS P-value thresholds (P_T): 5 ? 10 ?8 , 5 ? 10 ?7 , 5 ? 10 ?6 , 5 ? 10 ?5 , 5 ? 10 ?4 , 5 ? 10 ?3 , 0.05, 0.1, 0.2, 0.3, 0.4 and 0.5. A total of 100 principal components (PCs) were generated for the ALS sample using GCTA version 1.24.4. Using R version 3.2.2, a generalized linear model was applied to model the phenotype of individuals in the ALS dataset. PCs that had a significant effect on the phenotype (P<0.0005, Bonferroni-corrected for 100 PCs) were selected (PCs 1, 4, 5, 7, 8, 10, 11, 12, 14, 36, 49).

where y ‘s the phenotype regarding ALS dataset, ? ‘s the intercept of design that have a mountain ? for each and every variable x.

A beneficial Nagelkerke Roentgen dos well worth is acquired for every model and you may the newest baseline Nagelkerke R dos really worth is subtracted, leading to a beneficial ? informed me variance that relates to the fresh new sum from schizophrenia-dependent PRS to the phenotype regarding the ALS dataset. PRS investigation has also been performed in the permuted situation–handle investigation (step one,100 permutations, conserving circumstances–control ratio) to assess if the enhanced ? informed me difference is actually a true signal of the phenotype. ? said variances and you can P-viewpoints had been averaged around the permutation analyses.