The correlates of neonatal complement component 3 and 4 protein concentrations with a focus on psychiatric and autoimmune disorders.

Complement components have been linked to schizophrenia and autoimmune disorders. We examined the association between neonatal circulating C3 and C4 protein concentrations in 68,768 neonates and the risk of six mental disorders. We completed genome-wide association studies (GWASs) for C3 and C4 and applied the summary statistics in Mendelian randomization and phenome-wide association studies related to mental and autoimmune disorders. The GWASs for C3 and C4 protein concentrations identified 15 and 36 independent loci, respectively. We found no associations between neonatal C3 and C4 concentrations and mental disorders in the total sample (both sexes combined); however, post-hoc analyses found that a higher C3 concentration was associated with a reduced risk of schizophrenia in females. Mendelian randomization based on C4 summary statistics found an altered risk of five types of autoimmune disorders. Our study adds to our understanding of the associations between C3 and C4 concentrations and subsequent mental and autoimmune disorders.

The role of critical immune genes in brain disorders: insights from neuroimaging immunogenetics.

Genetic variants in the human leukocyte antigen and killer cell immunoglobulin-like receptor regions have been associated with many brain-related diseases, but how they shape brain structure and function remains unclear. To identify the genetic variants in HLA and KIR genes associated with human brain phenotypes, we performed a genetic association study of ∼30 000 European unrelated individuals using brain MRI phenotypes generated by the UK Biobank (UKB). We identified 15 HLA alleles in HLA class I and class II genes significantly associated with at least one brain MRI-based phenotypes (P < 5 × 10-8). These associations converged on several main haplotypes within the HLA. In particular, the human leukocyte antigen alleles within an ancestral haplotype 8.1 were associated with multiple MRI measures, including grey matter volume, cortical thickness (TH) and diffusion MRI (dMRI) metrics. These alleles have been strongly associated with schizophrenia. Additionally, associations were identified between HLA-DRB1*04∼DQA1*03:01∼DQB1*03:02 and isotropic volume fraction of diffusion MRI in multiple white matter tracts. This haplotype has been reported to be associated with Parkinson's disease. These findings suggest shared genetic associations between brain MRI biomarkers and brain-related diseases. Additionally, we identified 169 associations between the complement component 4 (C4) gene and imaging phenotypes. We found that C4 gene copy number was associated with cortical TH and dMRI metrics. No KIR gene copy numbers were associated with image-derived phenotypes at genome-wide threshold. To address the multiple testing burden in the phenome-wide association study, we performed a multi-trait association analysis using trait-based association test that uses extended Simes procedure and identified MRI image-specific associations. This study contributes to insight into how critical immune genes affect brain-related traits as well as the development of neurological and neuropsychiatric disorders.

Host genetic effects upon the early gut microbiota in a bovine model with graduated spectrum of genetic variation.

Multiple synergistic factors affect the development and composition of mammalian gut microbiota, but effects of host genetics remain unclear. To illuminate the role of host genetics on gut microbiota, we employed animals with a graduated spectrum of genetic variation with minimal environmental influences. We bred 228 calves with linearly varying breed composition from 100% Angus (Bos taurus) to 100% Brahman (Bos indicus), as a proxy for genetic variation, and then raised the offspring in the same environment with identical diets. We hypothesized each breed would harbor distinct gut microbiota due to genetic influence. We found that the gut microbiota of preweaning calves at 3 months old is significantly affected by host genetics, profoundly by paternal genome. We also demonstrate that single nucleotide polymorphisms in host mucin-encoding genes, critical for gut mucosal health, are significantly correlated with both breed composition and mucin-degrading gut bacteria. We further demonstrate host genetics indirectly changes gut microbiota composition via microbe-microbe interactions. These findings indicate a strong contribution by host genetics in shaping the gut microbiota during early life stages, shedding light on impact of animal breeding on gut microbiota, which is associated with animal growth and health.

Improved phylogenetic resolution for Y-chromosome Haplogroup O2a1c-002611.

Y-chromosome Haplogroup O2a1c-002611 is one of the dominant lineages of East Asians and Southeast Asians. However, its internal phylogeny remains insufficiently investigated. In this study, we genotyped 89 new highly informative single nucleotide polymorphisms (SNPs) in 305 individuals with Haplogroup O2a1c-002611 identified from 2139 Han Chinese males. Two major branches were identified, O2a1c1-F18 and O2a1c2-L133.2 and the first was further divided into two main subclades, O2a1c1a-F11 and O2a1c1b-F449, accounting for 11.13% and 2.20% of Han Chinese, respectively. In Haplogroup O2a1c1a-F11, we also determined seven sublineages with quite different frequency distributions in Han Chinese ranging from 0.187% to 3.553%, implying they might have different demographic history. The reconstructed haplogroup tree for all the major clades within Haplogroup O2a1c-002611 permits better resolution of male lineages in population studies of East Asia and Southeast Asia. The dataset generated in the present study are also valuable for forensic identification and paternity tests in China.