We calculated LD scores playing with LDSC v1

We calculated LD scores playing with LDSC v1

To help you imagine explained variance from Leeds hookup PRS into phenotype, set up a baseline linear relationship along with only sex and you will extreme Pcs just like the parameters is actually modelled basic:

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 rg estimation in pairs of traits this was the intersection of SNPs for 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 hS 2 estimation in ALS, and we also estimated hS 2 with a free intercept. For hS 2 estimation in all other traits and for rg estimation the intercept was a free parameter. We also estimated rg 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 . hS 2 was estimated for these meta-analysed permuted data using LD score regression (Supplementary Table 1).

Polygenic risk get study

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 (PT): 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, ? is the intercept of your design having a slope ? each variable x.

A great Nagelkerke Roentgen 2 well worth was obtained for every single design and you can this new baseline Nagelkerke R dos worth try subtracted, resulting in a beneficial ? explained difference one to relates to new share out of schizophrenia-mainly based PRS on phenotype from the ALS dataset. PRS investigation has also been performed from inside the permuted case–handle data (1,one hundred thousand permutations, keeping circumstances–manage ratio) to assess perhaps the improved ? told me difference are a real signal regarding the phenotype. ? explained variances and P-values have been averaged round the permutation analyses.

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