Fig 2: Concise summary of methods(1) iPSYCH 2012 case-cohort study: N (protein concentration) = 68,768; N (genotype) = 75,764. (2) iPSYCH 2015 expanded sample provided additional genotyped samples: N ∼ 56,000 samples. (3) C4A and C4B isotypes with or without HERV insertions were imputed (long and short, respectively) results in four alleles (AL, AS, BL, BS). See Tables S2 and S3. (4) Based on the imputed C4A, C4B, and HERV allele count, copy numbers were estimated. See Figure 3. (5) Based on Sekar et al.,9 brain C4A expression was estimated based on imputed C4 haplotypes. (6) We examined the association between variants associated with C4 and C3 protein concentration and mRNA expression in GTEx datasets, using summary-data-based Mendelian randomization (SMR). See Tables S12 and S16. (7) We examined the bidirectional association between variants associated with C4 and C3 protein concentration and summary statistics for a range of outcomes (see below) using generalized summary-data-based Mendelian randomization (GSMR). See Tables S22–S26. (8) We examined the association between variants associated with C4 and C3 protein concentration and a range of phenotypes identified in the UK Biobank. See Tables S27 and S28, and Figures S39 and S40. (9) The eight mental and neurological disorders were schizophrenia (SCZ), depression (DEP), bipolar disorder (BIP), autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), anorexia nervosa (AN), Alzheimer’s disease (ALZ), and amyotrophic lateral sclerosis (ALS). (10) The six autoimmune disorders were multiple sclerosis (MS), type 1 diabetes (T1D), Crohn’s disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RhA), and systemic lupus erythematosus (SLE).