Tourette syndrome is a heritable neurodevelopmental disorder whose pathophysiology remains unknown. Recent genome-wide association studies suggest that it is a polygenic disorder influenced by many genes of small effect. We tested whether these genes cluster in cellular function by applying gene-set analysis using expert curated sets of brain-expressed genes in the current largest available Tourette syndrome genome-wide association data set, involving 1285 cases and 4964 controls. The gene sets included specific synaptic, astrocytic, oligodendrocyte and microglial functions. We report association of Tourette syndrome with a set of genes involved in astrocyte function, specifically in astrocyte carbohydrate metabolism. This association is driven primarily by a subset of 33 genes involved in glycolysis and glutamate metabolism through which astrocytes support synaptic function. Our results indicate for the first time that the process of astrocyte-neuron metabolic coupling may be an important contributor to Tourette syndrome pathogenesis.

The relative influence of geography, currents, and environment on gene flow within sessile marine species remains an open question. Detecting subtle genetic differentiation at small scales is challenging in benthic populations due to large effective population sizes, general lack of resolution in genetic markers, and because barriers to dispersal often remain elusive. Marine lakes can circumvent confounding factors by providing discrete and replicated ecosystems. Using high-resolution double digest restriction-site-associated DNA sequencing (4826 Single Nucleotide Polymorphisms, SNPs), we genotyped populations of the sponge Suberites diversicolor (n = 125) to test the relative importance of spatial scales (1-1400 km), local environmental conditions, and permeability of seascape barriers in shaping population genomic structure. With the SNP dataset, we show strong intralineage population structure, even at scales <10 km (average F _ST = 0.63), which was not detected previously using single markers. Most variation was explained by differentiation between populations (AMOVA: 48.8%) with signatures of population size declines and bottlenecks per lake. Although the populations were strongly structured, we did not detect significant effects of geographic distance, local environments, or degree of connection to the sea on population structure, suggesting mechanisms such as founder events with subsequent priority effects may be at play. We show that the inclusion of morphologically cryptic lineages that can be detected with the COI marker can reduce the obtained SNP set by around 90%. Future work on sponge genomics should confirm that only one lineage is included. Our results call for a reassessment of poorly dispersing benthic organisms that were previously assumed to be highly connected based on low-resolution markers.

The folding of the human cerebral cortex is a highly genetically regulated process that allows for a much larger surface area to fit into the cranial vault and optimizes functional organization. Sulcal depth is a robust yet understudied measure of localized folding, previously associated with multiple neurodevelopmental disorders. Here, we report the first genome-wide association study of sulcal depth. Through the multivariate omnibus statistical test (MOSTest) applied to vertex-wise measures from 33,748 U.K. Biobank participants (mean age, 64.3 years; 52.0% female), we identified 856 genome-wide significant loci (P < 5 × 10⁻⁸). Comparisons with cortical thickness and surface area indicated that sulcal depth has higher locus yield, heritability, and effective sample size. There was a large amount of genetic overlap between these traits, with gene-based analyses indicating strong associations with neurodevelopmental processes. Our findings demonstrate sulcal depth is a promising neuroimaging phenotype that may enhance our understanding of cortical morphology.

Intelligence is highly heritable¹ and a major determinant of human health and well-being². Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence^3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

Intelligence is highly heritable¹ and a major determinant of human health and well-being². Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence^3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10^-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10^-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment.