The genetic and phenotypic correlates of neonatal Complement Component 3 and 4 protein concentrations with a focus on psychiatric and autoimmune disorders

The complement system, including complement components 3 and 4 (C3, C4), traditionally has been linked to innate immunity. More recently, complement components have also been implicated in brain development and the risk of schizophrenia. Based on a large, population-based case-cohort study, we measured the blood concentrations of C3 and C4 in 68,768 neonates. We found a strong correlation between the concentrations of C3 and C4 (phenotypic correlation = 0.65, P-value < 1.0x10-100, genetic correlation = 0.38, P-value = 1.9x10-35). A genome-wide association study (GWAS) for C4 protein concentration identified 36 independent loci, 30 of which were in or near the major histocompatibility complex on chromosome 6 (which includes the C4 gene), while six loci were found on six other chromosomes. A GWAS for C3 identified 15 independent loci, seven of which were located in the C3 gene on chromosome 19, and eight loci on five other chromosomes. We found no association between (a) measured neonatal C3 and C4 concentrations, imputed C4 haplotypes, or predicted C4 gene expression, with (b) schizophrenia (SCZ), bipolar disorder (BIP), depression (DEP), autism spectrum disorder, attention deficit hyperactivity disorder or anorexia nervosa diagnosed in later life. Mendelian randomisation (MR) suggested a small positive association between higher C4 protein concentration and an increased risk of SCZ, BIP, and DEP, but these findings did not persist in more stringent analyses. Evidence from MR supported causal relationships between C4 concentration and several autoimmune disorders: systemic lupus erythematosus (SLE, OR and 95% confidence interval, 0.37, 0.34 - 0.42); type-1 diabetes (T1D, 0.54, 0.50 - 0.58); multiple sclerosis (MS, 0.68, 0.63 - 0.74); rheumatoid arthritis (0.85, 0.80 - 0.91); and Crohns disease (1.26, 1.19 - 1.34). A phenome-wide association study (PheWAS) in UK Biobank confirmed that the genetic correlates of C4 concentration were associated a range of autoimmune disorders including coeliac disease, thyrotoxicosis, hypothyroidism, T1D, sarcoidosis, psoriasis, SLE and ankylosing spondylitis. We found no evidence of associations between C3 versus mental or autoimmune disorders based on either MR or PheWAS. In general, our results do not support the hypothesis that C4 is causally associated with the risk of SCZ (nor several other mental disorders). We provide new evidence to support the hypothesis that higher C4 concentration is associated with lower risks of autoimmune disorders.