Finemap-MiXeR: A variational Bayesian approach for genetic finemapping.

Genome-wide association studies (GWAS) implicate broad genomic loci containing clusters of highly correlated genetic variants. Finemapping techniques can select and prioritize variants within each GWAS locus which are more likely to have a functional influence on the trait. Here, we present a novel method, Finemap-MiXeR, for finemapping causal variants from GWAS summary statistics, controlling for correlation among variants due to linkage disequilibrium. Our method is based on a variational Bayesian approach and direct optimization of the Evidence Lower Bound (ELBO) of the likelihood function derived from the MiXeR model. After obtaining the analytical expression for ELBO's gradient, we apply Adaptive Moment Estimation (ADAM) algorithm for optimization, allowing us to obtain the posterior causal probability of each variant. Using these posterior causal probabilities, we validated Finemap-MiXeR across a wide range of scenarios using both synthetic data, and real data on height from the UK Biobank. Comparison of Finemap-MiXeR with two existing methods, FINEMAP and SuSiE RSS, demonstrated similar or improved accuracy. Furthermore, our method is computationally efficient in several aspects. For example, unlike many other methods in the literature, its computational complexity does not increase with the number of true causal variants in a locus and it does not require any matrix inversion operation. The mathematical framework of Finemap-MiXeR is flexible and may also be applied to other problems including cross-trait and cross-ancestry finemapping.

Sex and mental health are related to subcortical brain microstructure.

Some mental health problems such as depression and anxiety are more common in females, while others such as autism and attention deficit/hyperactivity (AD/H) are more common in males. However, the neurobiological origins of these sex differences are poorly understood. Animal studies have shown substantial sex differences in neuronal and glial cell structure, while human brain imaging studies have shown only small differences, which largely reflect overall body and brain size. Advanced diffusion MRI techniques can be used to examine intracellular, extracellular, and free water signal contributions and provide unique insights into microscopic cellular structure. However, the extent to which sex differences exist in these metrics of subcortical gray matter structures implicated in psychiatric disorders is not known. Here, we show large sex-related differences in microstructure in subcortical regions, including the hippocampus, thalamus, and nucleus accumbens in a large sample of young adults. Unlike conventional T1-weighted structural imaging, large sex differences remained after adjustment for age and brain volume. Further, diffusion metrics in the thalamus and amygdala were associated with depression, anxiety, AD/H, and antisocial personality problems. Diffusion MRI may provide mechanistic insights into the origin of sex differences in behavior and mental health over the life course and help to bridge the gap between findings from experimental, epidemiological, and clinical mental health research.

Baseline oxygen consumption decreases with cortical depth.

The cerebral cortex is organized in cortical layers that differ in their cellular density, composition, and wiring. Cortical laminar architecture is also readily revealed by staining for cytochrome oxidase-the last enzyme in the respiratory electron transport chain located in the inner mitochondrial membrane. It has been hypothesized that a high-density band of cytochrome oxidase in cortical layer IV reflects higher oxygen consumption under baseline (unstimulated) conditions. Here, we tested the above hypothesis using direct measurements of the partial pressure of O2 (pO2) in cortical tissue by means of 2-photon phosphorescence lifetime microscopy (2PLM). We revisited our previously developed method for extraction of the cerebral metabolic rate of O2 (CMRO2) based on 2-photon pO2 measurements around diving arterioles and applied this method to estimate baseline CMRO2 in awake mice across cortical layers. To our surprise, our results revealed a decrease in baseline CMRO2 from layer I to layer IV. This decrease of CMRO2 with cortical depth was paralleled by an increase in tissue oxygenation. Higher baseline oxygenation and cytochrome density in layer IV may serve as an O2 reserve during surges of neuronal activity or certain metabolically active brain states rather than reflecting baseline energy needs. Our study provides to our knowledge the first quantification of microscopically resolved CMRO2 across cortical layers as a step towards better understanding of brain energy metabolism.

Leveraging the adolescent brain cognitive development study to improve behavioral prediction from neuroimaging in smaller replication samples.

Neuroimaging is a popular method to map brain structural and functional patterns to complex human traits. Recently published observations cast doubt upon these prospects, particularly for prediction of cognitive traits from structural and resting state functional magnetic resonance imaging (MRI). We leverage baseline data from thousands of children in the Adolescent Brain Cognitive DevelopmentSM Study to inform the replication sample size required with univariate and multivariate methods across different imaging modalities to detect reproducible brain-behavior associations. We demonstrate that by applying multivariate methods to high-dimensional brain imaging data, we can capture lower dimensional patterns of structural and functional brain architecture that correlate robustly with cognitive phenotypes and are reproducible with only 41 individuals in the replication sample for working memory-related functional MRI, and ~ 100 subjects for structural and resting state MRI. Even with 100 random re-samplings of 100 subjects in discovery, prediction can be adequately powered with 66 subjects in replication for multivariate prediction of cognition with working memory task functional MRI. These results point to an important role for neuroimaging in translational neurodevelopmental research and showcase how findings in large samples can inform reproducible brain-behavior associations in small sample sizes that are at the heart of many research programs and grants.

Partitioning variance in cortical morphometry into genetic, environmental, and subject-specific components.

The relative contributions of genetic variation and experience in shaping the morphology of the adolescent brain are not fully understood. Using longitudinal data from 11,665 subjects in the ABCD Study, we fit vertex-wise variance components including family effects, genetic effects, and subject-level effects using a computationally efficient framework. Variance in cortical thickness and surface area is largely attributable to genetic influence, whereas sulcal depth is primarily explained by subject-level effects. Our results identify areas with heterogeneous distributions of heritability estimates that have not been seen in previous work using data from cortical regions. We discuss the biological importance of subject-specific variance and its implications for environmental influences on cortical development and maturation.

FEMA: Fast and efficient mixed-effects algorithm for large sample whole-brain imaging data.

The linear mixed-effects model (LME) is a versatile approach to account for dependence among observations. Many large-scale neuroimaging datasets with complex designs have increased the need for LME; however LME has seldom been used in whole-brain imaging analyses due to its heavy computational requirements. In this paper, we introduce a fast and efficient mixed-effects algorithm (FEMA) that makes whole-brain vertex-wise, voxel-wise, and connectome-wide LME analyses in large samples possible. We validate FEMA with extensive simulations, showing that the estimates of the fixed effects are equivalent to standard maximum likelihood estimates but obtained with orders of magnitude improvement in computational speed. We demonstrate the applicability of FEMA by studying the cross-sectional and longitudinal effects of age on region-of-interest level and vertex-wise cortical thickness, as well as connectome-wide functional connectivity values derived from resting state functional MRI, using longitudinal imaging data from the Adolescent Brain Cognitive DevelopmentSM Study release 4.0. Our analyses reveal distinct spatial patterns for the annualized changes in vertex-wise cortical thickness and connectome-wide connectivity values in early adolescence, highlighting a critical time of brain maturation. The simulations and application to real data show that FEMA enables advanced investigation of the relationships between large numbers of neuroimaging metrics and variables of interest while considering complex study designs, including repeated measures and family structures, in a fast and efficient manner. The source code for FEMA is available via: https://github.com/cmig-research-group/cmig_tools/.

Discrimination Between Benign and Malignant Lesions With Restriction Spectrum Imaging MRI in an Enriched Breast Cancer Screening Cohort.

BACKGROUND: Breast cancer screening with dynamic contrast-enhanced MRI (DCE-MRI) is recommended for high-risk women but has limitations, including variable specificity and difficulty in distinguishing cancerous (CL) and high-risk benign lesions (HRBL) from average-risk benign lesions (ARBL). Complementary non-invasive imaging techniques would be useful to improve specificity. PURPOSE: To evaluate the performance of a previously-developed breast-specific diffusion-weighted MRI (DW-MRI) model (BS-RSI3C) to improve discrimination between CL, HRBL, and ARBL in an enriched screening population. STUDY TYPE: Prospective. SUBJECTS: Exactly 187 women, either with mammography screening recommending additional imaging (N = 49) or high-risk individuals undergoing routine breast MRI (N = 138), before the biopsy. FIELD STRENGTH/SEQUENCE: Multishell DW-MRI echo planar imaging sequence with a reduced field of view at 3.0 T. ASSESSMENT: A total of 72 women had at least one biopsied lesion, with 89 lesions categorized into ARBL, HRBL, CL, and combined CLs and HRBLs (CHRLs). DW-MRI data were processed to produce apparent diffusion coefficient (ADC) maps, and estimate signal contributions (C1, C2, and C3-restricted, hindered, and free diffusion, respectively) from the BS-RSI3C model. Lesion regions of interest (ROIs) were delineated on DW images based on suspicious DCE-MRI findings by two radiologists; control ROIs were drawn in the contralateral breast. STATISTICAL TESTS: One-way ANOVA and two-sided t-tests were used to assess differences in signal contributions and ADC values among groups. P-values were adjusted using the Bonferroni method for multiple testing, P = 0.05 was used for the significance level. Receiver operating characteristics (ROC) curves and intra-class correlations (ICC) were also evaluated. RESULTS: C1, √C1C2, and log C 1 C 2 C 3 $$ \log \left(\frac{{\mathrm{C}}_1{\mathrm{C}}_2}{{\mathrm{C}}_3}\right) $$ were significantly different in HRBLs compared with ARBLs (P-values < 0.05). The log C 1 C 2 C 3 $$ \log \left(\frac{{\mathrm{C}}_1{\mathrm{C}}_2}{{\mathrm{C}}_3}\right) $$ had the highest AUC (0.821) in differentiating CHRLs from ARBLs, performing better than ADC (0.696), especially in non-mass enhancement (0.776 vs. 0.517). DATA CONCLUSION: This study demonstrated the BS-RSI3C could differentiate HRBLs from ARBLs in a screening population, and separate CHRLs from ARBLs better than ADC. TECHNICAL EFFICACY STAGE: 2.

Psychiatric disorders and brain white matter exhibit genetic overlap implicating developmental and neural cell biology.

Improved understanding of the shared genetic architecture between psychiatric disorders and brain white matter may provide mechanistic insights for observed phenotypic associations. Our objective is to characterize the shared genetic architecture of bipolar disorder (BD), major depression (MD), and schizophrenia (SZ) with white matter fractional anisotropy (FA) and identify shared genetic loci to uncover biological underpinnings. We used genome-wide association study (GWAS) summary statistics for BD (n = 413,466), MD (n = 420,359), SZ (n = 320,404), and white matter FA (n = 33,292) to uncover the genetic architecture (i.e., polygenicity and discoverability) of each phenotype and their genetic overlap (i.e., genetic correlations, overlapping trait-influencing variants, and shared loci). This revealed that BD, MD, and SZ are at least 7-times more polygenic and less genetically discoverable than average FA. Even in the presence of weak genetic correlations (range = -0.05 to -0.09), average FA shared an estimated 42.5%, 43.0%, and 90.7% of trait-influencing variants as well as 12, 4, and 28 shared loci with BD, MD, and SZ, respectively. Shared variants were mapped to genes and tested for enrichment among gene-sets which implicated neurodevelopmental expression, neural cell types, myelin, and cell adhesion molecules. For BD and SZ, case vs control tract-level differences in FA associated with genetic correlations between those same tracts and the respective disorder (rBD = 0.83, p = 4.99e-7 and rSZ = 0.65, p = 5.79e-4). Genetic overlap at the tract-level was consistent with average FA results. Overall, these findings suggest a genetic basis for the involvement of brain white matter aberrations in the pathophysiology of psychiatric disorders.

Identification of novel genomic risk loci shared between common epilepsies and psychiatric disorders.

Psychiatric disorders and common epilepsies are heritable disorders with a high comorbidity and overlapping symptoms. However, the causative mechanisms underlying this relationship are poorly understood. Here we aimed to identify overlapping genetic loci between epilepsy and psychiatric disorders to gain a better understanding of their comorbidity and shared clinical features. We analysed genome-wide association study data for all epilepsies (n = 44 889), genetic generalized epilepsy (n = 33 446), focal epilepsy (n = 39 348), schizophrenia (n = 77 096), bipolar disorder (n = 406 405), depression (n = 500 199), attention deficit hyperactivity disorder (n = 53 293) and autism spectrum disorder (n = 46 350). First, we applied the MiXeR tool to estimate the total number of causal variants influencing the disorders. Next, we used the conjunctional false discovery rate statistical framework to improve power to discover shared genomic loci. Additionally, we assessed the validity of the findings in independent cohorts, and functionally characterized the identified loci. The epilepsy phenotypes were considerably less polygenic (1.0 K to 3.4 K causal variants) than the psychiatric disorders (5.6 K to 13.9 K causal variants), with focal epilepsy being the least polygenic (1.0 K variants), and depression having the highest polygenicity (13.9 K variants). We observed cross-trait genetic enrichment between genetic generalized epilepsy and all psychiatric disorders and between all epilepsies and schizophrenia and depression. Using conjunctional false discovery rate analysis, we identified 40 distinct loci jointly associated with epilepsies and psychiatric disorders at conjunctional false discovery rate <0.05, four of which were associated with all epilepsies and 39 with genetic generalized epilepsy. Most epilepsy risk loci were shared with schizophrenia (n = 31). Among the identified loci, 32 were novel for genetic generalized epilepsy, and two were novel for all epilepsies. There was a mixture of concordant and discordant allelic effects in the shared loci. The sign concordance of the identified variants was highly consistent between the discovery and independent datasets for all disorders, supporting the validity of the findings. Gene-set analysis for the shared loci between schizophrenia and genetic generalized epilepsy implicated biological processes related to cell cycle regulation, protein phosphatase activity, and membrane and vesicle function; the gene-set analyses for the other loci were underpowered. The extensive genetic overlap with mixed effect directions between psychiatric disorders and common epilepsies demonstrates a complex genetic relationship between these disorders, in line with their bi-directional relationship, and indicates that overlapping genetic risk may contribute to shared pathophysiological and clinical features between epilepsy and psychiatric disorders.

Identification of novel genomic loci for anxiety symptoms and extensive genetic overlap with psychiatric disorders.

AIMS: Anxiety disorders are prevalent and anxiety symptoms (ANX) co-occur with many psychiatric disorders. We aimed to identify genomic loci associated with ANX, characterize its genetic architecture, and genetic overlap with psychiatric disorders. METHODS: We included a genome-wide association study of ANX (meta-analysis of UK Biobank and Million Veterans Program, n = 301,732), schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), and validated the findings in the Norwegian Mother, Father, and Child Cohort (n = 95,841). We employed the bivariate causal mixture model and local analysis of covariant association to characterize the genetic architecture including overlap between the phenotypes. Conditional and conjunctional false discovery rate analyses were performed to boost the identification of loci associated with anxiety and shared with psychiatric disorders. RESULTS: Anxiety was polygenic with 12.9k genetic variants and overlapped extensively with psychiatric disorders (4.1k-11.4k variants) with predominantly positive genetic correlations between anxiety and psychiatric disorders. We identified 119 novel loci for anxiety by conditioning on the psychiatric disorders, and loci shared between anxiety and MD n = 47 $$ \left(n=47\right) $$ , BIP n = 33 $$ \left(n=33\right) $$ , SCZ n = 71 $$ \left(n=71\right) $$ , ADHD n = 20 $$ \left(n=20\right) $$ , and ASD n = 5 $$ \left(n=5\right) $$ . Genes annotated to anxiety loci exhibit enrichment for a broader range of biological pathways including cell adhesion and neurofibrillary tangle compared with genes annotated to the shared loci. CONCLUSIONS: Anxiety is highly polygenic phenotype with extensive genetic overlap with psychiatric disorders, and we identified novel loci for anxiety implicating new molecular pathways. The shared genetic architecture may underlie the extensive cross-disorder comorbidity of anxiety, and the identified molecular underpinnings may lead to potential drug targets.

Quantitative MRI biomarker for classification of clinically significant prostate cancer: Calibration for reproducibility across echo times.

PURPOSE: The purpose of the present study is to develop a calibration method to account for differences in echo times (TE) and facilitate the use of restriction spectrum imaging restriction score (RSIrs) as a quantitative biomarker for the detection of clinically significant prostate cancer (csPCa). METHODS: This study included 197 consecutive patients who underwent MRI and biopsy examination; 97 were diagnosed with csPCa (grade group ≥ 2). RSI data were acquired three times during the same session: twice at minimum TE ~75 ms and once at TE = 90 ms (TEmin1, TEmin2, and TE90, respectively). A linear regression model was determined to match the C-maps of TE90 to the reference C-maps of TEmin1 within the interval ranging from 95th to 99th percentile of signal intensity within the prostate. RSIrs comparisons were made at the 98th percentile within each patient's prostate. We compared RSIrs from calibrated TE90 (RSIrsTE90corr) and uncorrected TE90 (RSIrsTE90) to RSIrs from reference TEmin1 (RSIrsTEmin1) and repeated TEmin2 (RSIrsTEmin2). Calibration performance was evaluated with sensitivity, specificity and area under the ROC curve (AUC). RESULTS: Scaling factors for C1, C2, C3, and C4 were estimated as 1.68, 1.33, 1.02, and 1.13, respectively. In non-csPCa cases, the 98th percentile of RSIrsTEmin2 and RSIrsTEmin1 differed by 0.27 ± 0.86SI (mean ± standard deviation), whereas RSIrsTE90 differed from RSIrsTEmin1 by 1.82 ± 1.20SI. After calibration, this bias was reduced to -0.51 ± 1.21SI, representing a 72% reduction in absolute error. For patients with csPCa, the difference was 0.54 ± 1.98SI between RSIrsTEmin2 and RSIrsTEmin1 and 2.28 ± 2.06SI between RSIrsTE90 and RSIrsTEmin1. After calibration, the mean difference decreased to -1.03SI, a 55% reduction in absolute error. At the Youden index for patient-level classification of csPCa (8.94SI), RSIrsTEmin1 has a sensitivity of 66% and a specificity of 72%. CONCLUSIONS: The proposed linear calibration method produces similar quantitative biomarker values for acquisitions with different TE, reducing TE-induced error by 72% and 55% for non-csPCa and csPCa, respectively.

Enrichment for clinical trials of early AD: Combining genetic risk factors and plasma p-tau as screening instruments.

INTRODUCTION: Identifying low-cost, minimally-invasive screening instruments for Alzheimer's disease (AD) trial enrichment will improve the efficiency of AD trials. METHODS: A total of 685 cognitively normal (CN) individuals and individuals with mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were grouped according to cutoffs of genetic risk factor (G) polygenic hazard score (PHS) and tau pathology (T) plasma phosphorylated tau-181 (p-tau181) into four groups: G+T+, G-T-, G+T-, and G-T+. We assessed the associations between group level and longitudinal cognitive decline and AD conversion. Power analyses compared the estimated sample size required to detect differences in cognitive decline. RESULTS: The G+T+ group was associated with faster cognitive decline and higher AD risk. Clinical trials enrolling G+T+ participants would benefit from significantly reduced sample sizes compared with similar trials using only single makers as an inclusion criterion. DISCUSSION: The combination of two low-cost, minimally-invasive measures-genetics and plasma biomarkers-would be a promising screening procedure for clinical trial enrollment. HIGHLIGHTS: Participants with unimpaired or mildly impaired cognition were grouped based on cutoffs on genetic risk factors (G: polygenic hazardous score [PHS]) and Alzheimer's pathology (T: baseline plasma phosphorylated tau-181 [p-tau181]). Participants with high PHSs and plasma p-tau181 levels (G+T+) were at risk of faster cognitive decline and AD progression. The combination of PHS and plasma p-tau181 could enhance clinical trial enrichment more effectively than using single biomarkers.

Task fMRI paradigms may capture more behaviorally relevant information than resting-state functional connectivity.

Characterizing the optimal fMRI paradigms for detecting behaviorally relevant functional connectivity (FC) patterns is a critical step to furthering our knowledge of the neural basis of behavior. Previous studies suggested that FC patterns derived from task fMRI paradigms, which we refer to as task-based FC, are better correlated with individual differences in behavior than resting-state FC, but the consistency and generalizability of this advantage across task conditions was not fully explored. Using data from resting-state fMRI and three fMRI tasks from the Adolescent Brain Cognitive Development Study ® (ABCD), we tested whether the observed improvement in behavioral prediction power of task-based FC can be attributed to changes in brain activity induced by the task design. We decomposed the task fMRI time course of each task into the task model fit (the fitted time course of the task condition regressors from the single-subject general linear model) and the task model residuals, calculated their respective FC, and compared the behavioral prediction performance of these FC estimates to resting-state FC and the original task-based FC. The FC of the task model fit was better than the FC of the task model residual and resting-state FC at predicting a measure of general cognitive ability or two measures of performance on the fMRI tasks. The superior behavioral prediction performance of the FC of the task model fit was content-specific insofar as it was only observed for fMRI tasks that probed similar cognitive constructs to the predicted behavior of interest. To our surprise, the task model parameters, the beta estimates of the task condition regressors, were equally if not more predictive of behavioral differences than all FC measures. These results showed that the observed improvement of behavioral prediction afforded by task-based FC was largely driven by the FC patterns associated with the task design. Together with previous studies, our findings highlighted the importance of task design in eliciting behaviorally meaningful brain activation and FC patterns.

Shared genetic loci between Alzheimer's disease and multiple sclerosis: Crossroads between neurodegeneration and immune system.

BACKGROUND: Neuroinflammation is involved in the pathophysiology of Alzheimer's disease (AD), including immune-linked genetic variants and molecular pathways, microglia and astrocytes. Multiple Sclerosis (MS) is a chronic, immune-mediated disease with genetic and environmental risk factors and neuropathological features. There are clinical and pathobiological similarities between AD and MS. Here, we investigated shared genetic susceptibility between AD and MS to identify putative pathological mechanisms shared between neurodegeneration and the immune system. METHODS: We analysed GWAS data for late-onset AD (N cases = 64,549, N controls = 634,442) and MS (N cases = 14,802, N controls = 26,703). Gaussian causal mixture modelling (MiXeR) was applied to characterise the genetic architecture and overlap between AD and MS. Local genetic correlation was investigated with Local Analysis of [co]Variant Association (LAVA). The conjunctional false discovery rate (conjFDR) framework was used to identify the specific shared genetic loci, for which functional annotation was conducted with FUMA and Open Targets. RESULTS: MiXeR analysis showed comparable polygenicities for AD and MS (approximately 1800 trait-influencing variants) and genetic overlap with 20% of shared trait-influencing variants despite negligible genetic correlation (rg = 0.03), suggesting mixed directions of genetic effects across shared variants. conjFDR analysis identified 16 shared genetic loci, with 8 having concordant direction of effects in AD and MS. Annotated genes in shared loci were enriched in molecular signalling pathways involved in inflammation and the structural organisation of neurons. CONCLUSIONS: Despite low global genetic correlation, the current results provide evidence for polygenic overlap between AD and MS. The shared loci between AD and MS were enriched in pathways involved in inflammation and neurodegeneration, highlighting new opportunities for future investigation.

Intelligence Polygenic Score Is More Predictive of Crystallized Measures: Evidence From the Adolescent Brain Cognitive Development (ABCD) Study.

Findings in adults have shown that crystallized measures of intelligence, which are more culturally sensitive than fluid intelligence measures, have greater heritability; however, these results have not been found in children. The present study used data from 8,518 participants between 9 and 11 years old from the Adolescent Brain Cognitive Development (ABCD) Study. We found that polygenic predictors of intelligence test performance (based on genome-wide association meta-analyses of data from 269,867 individuals) and of educational attainment (based on data from 1.1 million individuals) predicted neurocognitive performance. We found that crystallized measures were more strongly associated with both polygenic predictors than were fluid measures. This mirrored heritability differences reported previously in adults and suggests similar associations in children. This may be consistent with a prominent role of gene-environment correlation in cognitive development measured by crystallized intelligence tests. Environmental and experiential mediators may represent malleable targets for improving cognitive outcomes.

Heritability Estimation of Cognitive Phenotypes in the ABCD Study® Using Mixed Models.

Twin and family studies have historically aimed to partition phenotypic variance into components corresponding to additive genetic effects (A), common environment (C), and unique environment (E). Here we present the ACE Model and several extensions in the Adolescent Brain Cognitive Development℠ Study (ABCD Study®), employed using the new Fast Efficient Mixed Effects Analysis (FEMA) package. In the twin sub-sample (n = 924; 462 twin pairs), heritability estimates were similar to those reported by prior studies for height (twin heritability = 0.86) and cognition (twin heritability between 0.00 and 0.61), respectively. Incorporating SNP-derived genetic relatedness and using the full ABCD Study® sample (n = 9,742) led to narrower confidence intervals for all parameter estimates. By leveraging the sparse clustering method used by FEMA to handle genetic relatedness only for participants within families, we were able to take advantage of the diverse distribution of genetic relatedness within the ABCD Study® sample.

Shared genetic architecture between schizophrenia and subcortical brain volumes implicates early neurodevelopmental processes and brain development in childhood.

Patients with schizophrenia have consistently shown brain volumetric abnormalities, implicating both etiological and pathological processes. However, the genetic relationship between schizophrenia and brain volumetric abnormalities remains poorly understood. Here, we applied novel statistical genetic approaches (MiXeR and conjunctional false discovery rate analysis) to investigate genetic overlap with mixed effect directions using independent genome-wide association studies of schizophrenia (n = 130,644) and brain volumetric phenotypes, including subcortical brain and intracranial volumes (n = 33,735). We found brain volumetric phenotypes share substantial genetic variants (74-96%) with schizophrenia, and observed 107 distinct shared loci with sign consistency in independent samples. Genes mapped by shared loci revealed (1) significant enrichment in neurodevelopmental biological processes, (2) three co-expression clusters with peak expression at the prenatal stage, and (3) genetically imputed thalamic expression of CRHR1 and ARL17A was associated with the thalamic volume as early as in childhood. Together, our findings provide evidence of shared genetic architecture between schizophrenia and brain volumetric phenotypes and suggest that altered early neurodevelopmental processes and brain development in childhood may be involved in schizophrenia development.

Dissecting the shared genetic basis of migraine and mental disorders using novel statistical tools.

Migraine is three times more prevalent in people with bipolar disorder or depression. The relationship between schizophrenia and migraine is less certain although glutamatergic and serotonergic neurotransmission are implicated in both. A shared genetic basis to migraine and mental disorders has been suggested but previous studies have reported weak or non-significant genetic correlations and five shared risk loci. Using the largest samples to date and novel statistical tools, we aimed to determine the extent to which migraine's polygenic architecture overlaps with bipolar disorder, depression and schizophrenia beyond genetic correlation, and to identify shared genetic loci. Summary statistics from genome-wide association studies were acquired from large-scale consortia for migraine (n cases = 59 674; n controls = 316 078), bipolar disorder (n cases = 20 352; n controls = 31 358), depression (n cases = 170 756; n controls = 328 443) and schizophrenia (n cases = 40 675, n controls = 64 643). We applied the bivariate causal mixture model to estimate the number of disorder-influencing variants shared between migraine and each mental disorder, and the conditional/conjunctional false discovery rate method to identify shared loci. Loci were functionally characterized to provide biological insights. Univariate MiXeR analysis revealed that migraine was substantially less polygenic (2.8 K disorder-influencing variants) compared to mental disorders (8100-12 300 disorder-influencing variants). Bivariate analysis estimated that 800 (SD = 300), 2100 (SD = 100) and 2300 (SD = 300) variants were shared between bipolar disorder, depression and schizophrenia, respectively. There was also extensive overlap with intelligence (1800, SD = 300) and educational attainment (2100, SD = 300) but not height (1000, SD = 100). We next identified 14 loci jointly associated with migraine and depression and 36 loci jointly associated with migraine and schizophrenia, with evidence of consistent genetic effects in independent samples. No loci were associated with migraine and bipolar disorder. Functional annotation mapped 37 and 298 genes to migraine and each of depression and schizophrenia, respectively, including several novel putative migraine genes such as L3MBTL2, CACNB2 and SLC9B1. Gene-set analysis identified several putative gene sets enriched with mapped genes including transmembrane transport in migraine and schizophrenia. Most migraine-influencing variants were predicted to influence depression and schizophrenia, although a minority of mental disorder-influencing variants were shared with migraine due to the difference in polygenicity. Similar overlap with other brain-related phenotypes suggests this represents a pool of 'pleiotropic' variants that influence vulnerability to diverse brain-related disorders and traits. We also identified specific loci shared between migraine and each of depression and schizophrenia, implicating shared molecular mechanisms and highlighting candidate migraine genes for experimental validation.

Associations between MRI-assessed locus coeruleus integrity and cortical gray matter microstructure.

The locus coeruleus (LC) is one of the earliest sites of tau pathology, making it a key structure in early Alzheimer's disease (AD) progression. As the primary source of norepinephrine for the brain, reduced LC integrity may have negative consequences for brain health, yet macrostructural brain measures (e.g. cortical thickness) may not be sensitive to early stages of neurodegeneration. We therefore examined whether LC integrity was associated with differences in cortical gray matter microstructure among 435 men (mean age = 67.5; range = 62-71.7). LC structural integrity was indexed by contrast-to-noise ratio (LCCNR) from a neuromelanin-sensitive MRI scan. Restriction spectrum imaging (RSI), an advanced multi-shell diffusion technique, was used to characterize cortical microstructure, modeling total diffusion in restricted, hindered, and free water compartments. Higher LCCNR (greater integrity) was associated with higher hindered and lower free water diffusion in multiple cortical regions. In contrast, no associations between LCCNR and cortical thickness survived correction. Results suggest lower LC integrity is associated with patterns of cortical microstructure that may reflect a reduction in cytoarchitectural barriers due to broader neurodegenerative processes. These findings highlight the potential utility for LC imaging and advanced diffusion measures of cortical microstructure in assessing brain health and early identification of neurodegenerative processes.

Genome-wide analyses reveal novel opioid use disorder loci and genetic overlap with schizophrenia, bipolar disorder, and major depression.

Opioid use disorder (OUD) and mental disorders are often comorbid, with increased morbidity and mortality. The causes underlying this relationship are poorly understood. Although these conditions are highly heritable, their shared genetic vulnerabilities remain unaccounted for. We applied the conditional/conjunctional false discovery rate (cond/conjFDR) approach to analyse summary statistics from independent genome wide association studies of OUD, schizophrenia (SCZ), bipolar disorder (BD) and major depression (MD) of European ancestry. Next, we characterized the identified shared loci using biological annotation resources. OUD data were obtained from the Million Veteran Program, Yale-Penn and Study of Addiction: Genetics and Environment (SAGE) (15 756 cases, 99 039 controls). SCZ (53 386 cases, 77 258 controls), BD (41 917 cases, 371 549 controls) and MD (170 756 cases, 329 443 controls) data were provided by the Psychiatric Genomics Consortium. We discovered genetic enrichment for OUD conditional on associations with SCZ, BD, MD and vice versa, indicating polygenic overlap with identification of 14 novel OUD loci at condFDR < 0.05 and 7 unique loci shared between OUD and SCZ (n = 2), BD (n = 2) and MD (n = 7) at conjFDR < 0.05 with concordant effect directions, in line with estimated positive genetic correlations. Two loci were novel for OUD, one for BD and one for MD. Three OUD risk loci were shared with more than one psychiatric disorder, at DRD2 on chromosome 11 (BD and MD), at FURIN on chromosome 15 (SCZ, BD and MD) and at the major histocompatibility complex region (SCZ and MD). Our findings provide new insights into the shared genetic architecture between OUD and SCZ, BD and MD, indicating a complex genetic relationship, suggesting overlapping neurobiological pathways.