Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

Abstract

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10^-4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10^-7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.

Figure 1. Genetic correlation between ALS and eight secondary traits.

Error bars indicating 95% confidence intervals and P-values were calculated by the LD score regression software using a block jackknife procedure. Secondary traits are: AD, Alzheimer's disease; ADHD, attention deficit-hyperactivity disorder; ASD, autism spectrum disorder; BPD, bipolar disorder; MDD, major depressive disorder; MS, multiple sclerosis; SCZ, schizophrenia.

Figure 2. Analysis of PRS for schizophrenia in a target sample of 10,032 ALS cases and 16,627 healthy controls.

P-value thresholds (P_T) for schizophrenia SNPs are shown on the x axis, where the number of SNPs increases with a more lenient P_T. Δ Explained variances (Nagelkerke R², shown as a %) of a generalized linear model including schizophrenia-based PRS versus a baseline model without polygenic scores (blue bars) are shown for each P_T. −Log₁₀ P-values of Δ explained variance per P_T (red dots) represent P-values from the binomial logistic regression of ALS phenotype on PRS, accounting for LD (Supplementary Table 4) and including sex and significant principal components as covariates (Supplementary Fig. 2). Values are provided in Supplementary Table 5.

Figure 3. Odds ratio for ALS by PRS deciles for schizophrenia.

The figure applies to schizophrenia P-value threshold (P_T)=0.2. The PRS for this threshold were converted to ten deciles containing near identical numbers of individuals. Decile 1 contained the lowest scores and decile 10 contained the highest scores, where decile 1 was the reference and deciles 2–10 were dummy variables to contrast to decile 1 for OR calculation. The case:control ratio per decile is indicated with grey bars. Error bars indicate 95% confidence intervals. Significant differences from decile 1 were determined by logistic regression of ALS phenotype on PRS decile, including sex and principal components as covariates and are indicated by *P<0.05 or ***P<0.001.

Figure 4. Pleiotropy-informed ALS risk loci determined by analysis of cFDR in ALS GWAS P-values given schizophrenia GWAS P-values (cFDR_ALS|SCZ).

Each point denotes a SNP; its x axis position corresponds to its chromosomal location and its height indicates the extent of association with ALS by cFDR analysis. The solid line indicates the threshold cFDR=0.01. Any gene whose role in ALS is already established is in bold. A complete list of all loci at cFDR⩽0.05 is provided in Supplementary Table 8.