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Epigenetic modifications influenced by environmental exposures are molecular sources of phenotypic heterogeneity found in schizophrenia and bipolar disorder and may contribute to shared etiopathogenetic mechanisms of these two disorders. Newborns who experienced birth asphyxia have suffered reduced oxygen delivery to the brain around the time of birth, which increases the risk of later psychiatric diagnosis. This study aimed to investigate DNA methylation in blood cells for associations with a history of birth asphyxia, a neurologically harmful condition occurring within the biological environment of birth. We utilized prospective data from the Medical Birth Registry of Norway to identify incidents of birth asphyxia in 643 individuals with schizophrenia or bipolar disorder and 676 healthy controls. We performed an epigenome wide association study to distinguish differentially methylated positions associated with birth asphyxia. We found an interaction between methylation and exposure to birth asphyxia on case–control status, wherein having a history of birth asphyxia was associated with an increase of methylation in healthy controls and a decrease of methylation in patients on 4 regions of DNA important for brain development and function. The differentially methylated regions were observed in genes involved in oligodendrocyte survival and axonal myelination and functional recovery (LINGO3); assembly, maturation and maintenance of the brain (BLCAP;NNAT and NANOS2) and axonal transport processes and neural plasticity (SLC2A14). These findings are consistent with the notion that an opposite epigenetic response to birth asphyxia, in patients compared with controls, may contribute to molecular mechanisms of risk for schizophrenia and bipolar disorder.

The placenta plays a role in fetal brain development, and pregnancy and birth complications can be signs of placental dysfunction. Birth asphyxia is associated with smaller head size and higher risk of developing schizophrenia (SZ), but whether birth asphyxia and placental genetic risk factors associated with SZ are related and how they might impact brain development is unclear. 433 adult patients with SZ and 870 healthy controls were clinically evaluated and underwent brain magnetic resonance imaging. Pregnancy and birth information were obtained from the Medical Birth Registry of Norway. Polygenic risk scores (PRS) from the latest genome-wide association study in SZ were differentiated into placental PRS (PlacPRS) and non-placental PRS. If the interaction between PRSs and birth asphyxia on case-control status was significant, neonatal head circumference (nHC) and adult intracranial volume (ICV) were further evaluated with these variables using multiple regression. PlacPRS in individuals with a history of birth asphyxia was associated with a higher likelihood of being a patient with SZ (t=2.10, p=.018). We found a significant interaction between PlacPRS and birth asphyxia on nHC in the whole sample (t=-2.14, p=.017), with higher placental PRS for SZ associated with lower nHC in those with birth asphyxia. This relationship was specific to males (t=-2.41, p=.010) and also found with their adult ICV (t=-1.97, p=.028). These findings suggest that placental pathophysiology and birth asphyxia may affect early and late trajectories of brain development, particularly in males with a higher vulnerability to SZ. This knowledge might lead to new strategies of treatment and prevention in SZ.

The etiology of anorexia nervosa (AN) remains elusive. Recent genome-wide association studies identified the first genes liked to AN which reached genome-wide significance, although our understanding of how these genes confer risk remains preliminary. Here, we leverage the Allen Human Brain Atlas to characterize the spatially distributed gene expression patterns of genes linked to AN in the non-disordered human brain, developing whole-brain maps of AN gene expression. We found that genes associated with AN are most expressed in the brain, relative to all other body tissue types, and demonstrate gene-specific expression patterns which extend to cerebellar, limbic and basal ganglia structures in particular. fMRI meta-analyses reveal that AN gene expression maps correspond with functional brain activity involved in processing and anticipating appetitive and aversive cues. Findings offer novel insights around putative mechanisms through which genes associated with AN may confer risk.

Treatment resistant schizophrenia (TRS) is characterized by repeated treatment failure with antipsychotics. A recent genome-wide association study (GWAS) of TRS showed a polygenic architecture, but no significant loci were identified. Clozapine is shown to be the superior drug in terms of clinical effect in TRS; at the same time it has a serious side effect profile, including weight gain. Here, we sought to increase power for genetic discovery and improve polygenic prediction of TRS, by leveraging genetic overlap with Body Mass Index (BMI). We analysed GWAS summary statistics for TRS and BMI applying the conditional false discovery rate (cFDR) framework. We observed cross-trait polygenic enrichment for TRS conditioned on associations with BMI. Leveraging this cross-trait enrichment, we identified 2 novel loci for TRS at cFDR MAP2K1 and ZDBF2. Further, polygenic prediction based on the cFDR analysis explained more variance in TRS when compared to the standard TRS GWAS. These findings highlight putative molecular pathways which may distinguish TRS patients from treatment responsive patients. Moreover, these findings confirm that shared genetic mechanisms influence both TRS and BMI and provide new insights into the biological underpinnings of metabolic dysfunction and antipsychotic treatment.

Iron is an important element required for the body to function properly; however, hemochromatosis, an excess of iron in healthy tissue, can lead to cell damage. C282Y is a genetic variant prevalent in European populations, which is known to increase iron levels in the body and is responsible for most hemochromatosis cases. Recent work from our group analyzing brain Magnetic Resonance (MR) images established, in a large sample of older adults, that individuals who were homozygous for C282Y showed evidence consistent with substantial iron deposition localized to brain regions related to the motor system. These individuals also had nearly two-fold increased risk for developing movement disorders, like Parkinson’s Disease (PD). Here, we describe the broader polygenic architecture of this novel endophenotype - the “hemochromatosis brain.” This multivariate MRI phenotype captures average brain-wide differences of C282Y homozygote individuals and may reflect consequences of iron deposition localized to motor circuits. To do this we trained a classifier in a sample of 960 individuals from the UKBiobank to distinguish C282Y homozygotes from other genotypes using phenotypes derived from MR images sensitive to iron. This classifier was then applied to an independent set of 35,283 individuals for which MRI were available in the UKBiobank. This generated, for each individual, a PolyVoxel Score (PVS) that captures variation in MRI phenotypes associated previously with C282Y homozygosity and may reflect the degree of brain-specific iron deposition or other disease mechanisms. In this independent set we showed the PVS significantly predicted risk for PD (OR=1.37, p=0.0089). Studying the genetics of the “hemochromatosis brain” we conducted a GWAS on the PVS to show it to be highly heritablewith 43 genome-wide significant loci. Many of these signals are proximal to genes known to be involved in iron homeostasis (TF, rs6794370, p=2.43×10−81; HFE rs1800562, p=6.93×10−75; TMPRSS6, rs2413450, p=2.52×10−50). Discovered genomic variants overlapped with previous GWAS studies of iron/red blood cells, non-iron blood markers and brain and cognitive traits. Cell type enrichment implicated glial cells to be the principal cell class related to the PVS GWAS signal, in line with previous work finding that these cells to have the highest iron concentrations in the brain. Finally, tissue-specific analysis identified the substantia nigra and hippocampus to have enriched epigenetic markers to our GWAS findings. We have made available a python program to generate the PVS from MRI scans. In conclusion, we have shown that the multivariate MRI phenotype associated with C282Y homozygosity is, in fact, highly heritable, polygenic, and represents a novel brain endophenotype of PD. Our unique approach of combining classical forward and reverse genetics approaches to define and describe potentially disease mediating endophenotypes could be applied more broadly to other clinically relevant disorders.

ImportanceHereditary hemochromatosis (HH) is an autosomal recessive genetic disorder that leads to iron overload. Conflicting results from previous research has led some to believe the brain is spared the toxic effects of iron in HH.ObjectiveTo test the association of the strongest genetic risk variant for HH on brainwide measures sensitive to iron deposition and the rates of movement disorders in a substantially larger sample than previous studies of its kind.Design, setting, and participantsThis cross-sectional retrospective study included participants from the UK Biobank, a population-based sample. Genotype, health record, and neuroimaging data were collected from January 2006 to May 2021. Data analysis was conducted from January 2021 to April 2022. Disorders tested included movement disorders (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10], codes G20-G26), abnormalities of gait and mobility (ICD-10 codes R26), and other disorders of the nervous system (ICD-10 codes G90-G99).ExposuresHomozygosity for p.C282Y, the largest known genetic risk factor for HH.Main outcomes and measuresT2-weighted and T2* signal intensity from brain magnetic resonance imaging scans, measures sensitive to iron deposition, and clinical diagnosis of neurological disorders.ResultsThe total cohort consisted of 488 288 individuals (264 719 female; ages 49-87 years, largely northern European ancestry), 2889 of whom were p.C282Y homozygotes. The neuroimaging analysis consisted of 836 individuals: 165 p.C282Y homozygotes (99 female) and 671 matched controls (399 female). A total of 206 individuals were excluded from analysis due to withdrawal of consent. Neuroimaging analysis showed that p.C282Y homozygosity was associated with decreased T2-weighted and T2* signal intensity in subcortical motor structures (basal ganglia, thalamus, red nucleus, and cerebellum; Cohen d >1) consistent with substantial iron deposition. Across the whole UK Biobank (2889 p.C282Y homozygotes, 485 399 controls), we found a significantly increased prevalence for movement disorders in male homozygotes (OR, 1.80; 95% CI, 1.28-2.55; P = .001) but not female individuals (OR, 1.09; 95% CI, 0.70-1.73; P = .69). Among the 31 p.C282Y male homozygotes with a movement disorder, only 10 had a concurrent HH diagnosis.Conclusions and relevanceThese findings indicate increased iron deposition in subcortical motor circuits in p.C282Y homozygotes and confirm an increased association with movement disorders in male homozygotes. Early treatment in HH effectively prevents the negative consequences of iron overload in the liver and heart. Our work suggests that screening for p.C282Y homozygosity in high-risk individuals also has the potential to reduce brain iron accumulation and to reduce the risk of movement disorders among male individuals who are homozygous for this mutation.

Mechanisms underpinning neurotypical age-related variations in cortical thickness in the human brain remain insufficiently specified. Here we used cell-specific marker genes, followed by gene ontology and enrichment analyses, to quantify the association between gene-expression levels and inter-regional age-related variations in neurotypical cortical thinning using multicohort neuroimaging data from 14,248 individuals ages 4-89 years. We found that early-life (60 years) were associated with distinct patterns of association between inter-regional profiles of cortical thickness and expression profiles of markers genes for CA1 and S1 pyramidal cells, astrocytes, and microglia. Gene ontology and enrichment analyses indicated each of the three life-stages was associated with different biological processes and cellular components; these related to synaptic modeling in early life, neurotransmission in mid-life, and neurodegeneration in late-life. These findings provide mechanistic insights on age-related cortical thinning during typical development and ageing.

Using genome-wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s (PD) or Alzheimer’s (AD) disease versus controls across ancestry groups. A shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2x10-13; AD: OR=0.91[0.89; 0.93]; p=1.8x10-22), and with a protective HLA association recently reported in amyotrophic lateral sclerosis (ALS). Hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03, and absent for HLA-DRB1*04:05. The same signal was associated with decreased neurofibrillary tangles (but not neuritic plaque density) in postmortem brains and was more strongly associated with tau levels than Aβ42 levels in the cerebrospinal fluid. Finally, protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation. An HLA-DRB1*04-mediated adaptive immune response, potentially against tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues.

Objective Autism Spectrum Disorder (ASD) is a highly heritable condition with a large variation in cognitive function. Here we investigated the shared genetic architecture between cognitive traits (intelligence (INT) and educational attainment (EDU)), and risk loci jointly associated with ASD and the cognitive traits. Methods We included data from genome-wide association studies (GWAS) of INT (n = 269,867), EDU (n = 766,345) and ASD (cases n = 18,381, controls n = 27,969). We used the bivariate causal mixture model (MiXeR) to estimate the total number of shared genetic variants, and conditional and conjunctional false discovery rate (cond/conjFDR) to identify specific overlapping loci. Results The MiXeR indicated 12.7k genetic variants associated with ASD, with 12.0k shared with EDU and 11.1k shared with INT (Dice: 0.90–0.91), with both positive and negative relationships within overlapping variants. The majority (59%-68%) of estimated shared loci have concordant effect directions, with a positive, albeit modest, genetic correlation between ASD and EDU (rg=0.21, p = 2e-13) and INT (rg=0.22, p = 4e-12). We discovered 43 loci jointly associated with ASD and cognitive traits (conjFDR