We determined LD ratingramss having fun with LDSC v1

We determined LD ratingramss having fun with LDSC v1

To estimate explained difference away from PRS into phenotype, set up a baseline linear dating including just sex and you may significant Personal computers because variables was 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 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 rating 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 (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 the ALS dataset, ? ‘s the intercept of the design which have a slope ? for each and every adjustable x.

An excellent Nagelkerke R dos worth was acquired each design and you may this new baseline Nagelkerke R 2 well worth try deducted, ultimately causing a ? explained variance one to describes the fresh sum regarding schizophrenia-created PRS on phenotype regarding the ALS dataset. Knoxville local hookup app free PRS data has also been did into the permuted instance–manage studies (step 1,100 permutations, keeping instance–manage proportion) to evaluate whether or not the enhanced ? explained variance is actually a genuine rule for the phenotype. ? informed me variances and P-viewpoints were averaged across the permutation analyses.

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