No abstract

The first genome-wide study of sulcal depth shows that it is highly genetically discoverable, associated with neurodevelopment.

Psychiatric disorders are complex, heritable, and highly polygenic. Supported by findings of abnormalities in functional magnetic resonance imaging (fMRI) based measures of brain connectivity, current theoretical and empirical accounts have conceptualized them as disorders of brain connectivity and dysfunctional integration of brain signaling, however, the extent to which these findings reflect common genetic factors remains unclear. Here, we performed a multivariate genome-wide association analysis of fMRI-based functional brain connectivity in a sample of 30,701 individuals from the UK Biobank and investigated the shared genetic determinants with seven major psychiatric disorders. The analysis revealed significant genetic overlap between functional brain connectivity and schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, autism spectrum disorder, anxiety, and major depression, adding further genetic support for the dysconnectivity hypothesis of psychiatric disorders and identifying potential genetic and functional targets for future studies.

The molecular determinants of tissue composition of the human brain remain largely unknown. Recent genome-wide association studies (GWAS) on this topic have had limited success due to methodological constraints. Here, we apply advanced whole-brain analyses on multi-shell diffusion imaging data and multivariate GWAS to two large scale imaging genetic datasets (UK Biobank and the Adolescent Brain Cognitive Development study) to identify and validate genetic association signals. We discover 503 unique genetic loci that have impact on multiple regions of human brain. Among them, more than 79% are validated in either of two large-scale independent imaging datasets. Key molecular pathways involved in axonal growth, astrocyte-mediated neuroinflammation, and synaptogenesis during development are found to significantly impact the measured variations in tissue-specific imaging features. Our results shed new light on the biological determinants of brain tissue composition and their potential overlap with the genetic basis of neuropsychiatric disorders.

IMPORTANCE Hereditary 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.OBJECTIVE To 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 PARTICIPANTS This 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,, codes G20-G26), abnormalities of gait and mobility (ICD-10 codes R26), and other disorders of the nervous system (ICD-10 codes G90-G99).EXPOSURES Homozygosity for p.C282Y, the largest known genetic risk factor for HH.MAIN OUTCOMES AND MEASURES T2-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.