Genetic variants for head size share genes and pathways with cancer.

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

Obesity and the cerebral cortex: Underlying neurobiology in mice and humans.

Obesity is a major modifiable risk factor for Alzheimer's disease (AD), characterized by progressive atrophy of the cerebral cortex. The neurobiology of obesity contributions to AD is poorly understood. Here we show with in vivo MRI that diet-induced obesity decreases cortical volume in mice, and that higher body adiposity associates with lower cortical volume in humans. Single-nuclei transcriptomics of the mouse cortex reveals that dietary obesity promotes an array of neuron-adverse transcriptional dysregulations, which are mediated by an interplay of excitatory neurons and glial cells, and which involve microglial activation and lowered neuronal capacity for neuritogenesis and maintenance of membrane potential. The transcriptional dysregulations of microglia, more than of other cell types, are like those in AD, as assessed with single-nuclei cortical transcriptomics in a mouse model of AD and two sets of human donors with the disease. Serial two-photon tomography of microglia demonstrates microgliosis throughout the mouse cortex. The spatial pattern of adiposity-cortical volume associations in human cohorts interrogated together with in silico bulk and single-nucleus transcriptomic data from the human cortex implicated microglia (along with other glial cells and subtypes of excitatory neurons), and it correlated positively with the spatial profile of cortical atrophy in patients with mild cognitive impairment and AD. Thus, multi-cell neuron-adverse dysregulations likely contribute to the loss of cortical tissue in obesity. The dysregulations of microglia may be pivotal to the obesity-related risk of AD.

Prediabetic HbA1c and Cortical Atrophy: Underlying Neurobiology.

OBJECTIVE: To investigate the relationship between blood glycated hemoglobin (HbA1c) and cerebral cortical thickness (CT) and identify potential cellular mechanisms involved. RESEARCH DESIGN AND METHODS: A cohort of 30,579 adults age 45 to 81 (mean ± SD: 64 ± 7.5) years with available data on brain MRI and blood HbA1c levels was analyzed. The relationship between HbA1c and CT was probed using independent spatial profiles of cell-specific gene expression. Lastly, a genome-wide association study was conducted on the shared variance between HbA1c and CT. RESULTS: The HbA1c-CT association was noncontinuous, emerging negatively within the prediabetic range (39.6 mmol/mol). This association was strongest in brain regions with higher expression of genes specific to excitatory neurons and lower expression of genes specific to astrocytes and microglia. A significant locus implicated mitochondrial maintenance and ATP generation. CONCLUSIONS: Effective glycemia control at prediabetic levels is warranted to preserve brain health and prevent prediabetes-related neurobiologic perturbations.

Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease.

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.

A biologically informed polygenic score of neuronal plasticity moderates the association between cognitive aptitudes and cortical thickness in adolescents.

Although many studies of the adolescent brain identified positive associations between cognitive abilities and cortical thickness, little is known about mechanisms underlying such brain-behavior relationships. With experience-induced plasticity playing an important role in shaping the cerebral cortex throughout life, it is likely that some of the inter-individual variations in cortical thickness could be explained by genetic variations in relevant molecular processes, as indexed by a polygenic score of neuronal plasticity (PGS-NP). Here, we studied associations between PGS-NP, cognitive abilities, and thickness of the cerebral cortex, estimated from magnetic resonance images, in the Saguenay Youth Study (SYS, 533 females, 496 males: age=15.0 ± 1.8 years of age; cross-sectional), and the IMAGEN Study (566 females, 556 males; between 14 and 19 years; longitudinal). Using Gene Ontology, we first identified 199 genes implicated in neuronal plasticity, which mapped to 155,600 single nucleotide polymorphisms (SNPs). Second, we estimated their effect sizes from an educational attainment meta-GWAS to build a PGS-NP. Third, we examined a possible moderating role of PGS-NP in the relationship between performance intelligence quotient (PIQ), and its subtests, and the thickness of 34 cortical regions. In SYS, we observed a significant interaction between PGS-NP and object assembly vis-à-vis thickness in male adolescents (p = 0.026). A median-split analysis showed that, in males with a 'high' PGS-NP, stronger associations between object assembly and thickness were found in regions with larger age-related changes in thickness (r = 0.55, p = 0.00075). Although the interaction between PIQ and PGS-NP was non-significant (p = 0.064), we performed a similar median-split analysis. Again, in the high PGS-NP males, positive associations between PIQ and thickness were observed in regions with larger age-related changes in thickness (r = 0.40, p = 0.018). In the IMAGEN cohort, we did not replicate the first set of results (interaction between PGS-NP and cognitive abilities via-a-vis cortical thickness) while we did observe the same relationship between the brain-behaviour relationship and (longitudinal) changes in cortical thickness (Matrix reasoning: r = 0.63, p = 6.5e-05). No statistically significant results were observed in female adolescents in either cohort. Overall, these cross-sectional and longitudinal results suggest that molecular mechanisms involved in neuronal plasticity may contribute to inter-individual variations of cortical thickness related to cognitive abilities during adolescence in a sex-specific manner.

Disentangling the influences of parental genetics on offspring's cognition, education, and psychopathology via genetic and phenotypic pathways.

BACKGROUND: Specific pathways of intergenerational transmission of behavioral traits remain unclear. Here, we aim to investigate how parental genetics influence offspring cognition, educational attainment, and psychopathology in youth. METHODS: Participants for the discovery sample were 2,189 offspring (aged 6-14 years), 1898 mothers and 1,017 fathers who underwent genotyping, psychiatric, and cognitive assessments. We calculated polygenic scores (PGS) for cognition, educational attainment, attention-deficit hyperactivity disorder (ADHD), and schizophrenia for the trios. Phenotypes studied included educational and cognitive measures, ADHD and psychotic symptoms. We used a stepwise approach and multiple mediation models to analyze the effect of parental PGS on offspring traits via offspring PGS and parental phenotype. Significant results were replicated in a sample of 1,029 adolescents, 363 mothers, and 307 fathers. RESULTS: Maternal and paternal PGS for cognition influenced offspring general intelligence and executive function via offspring PGS (genetic pathway) and parental education (phenotypic pathway). Similar results were found for parental PGS for educational attainment and offspring reading and writing skills. These pathways fully explained associations between parental PGS and offspring phenotypes, without residual direct association. Associations with maternal, but not paternal, PGS were replicated. No associations were found between parental PGS for psychopathology and offspring specific symptoms. CONCLUSIONS: Our findings indicate that parental genetics influences offspring cognition and educational attainment by genetic and phenotypic pathways, suggesting the expression of parental phenotypes partially explain the association between parental genetic risk and offspring outcomes. Multiple mediations might represent an effective approach to disentangle distinct pathways for intergenerational transmission of behavioral traits.

Association between metabolic syndrome and mortality in patients with COVID-19: A nationwide cohort study.

OBJECTIVES: We investigated the association between metabolic syndrome (MetS) and mortality among coronavirus disease 2019 (COVID-19) patients in Korea. METHODS: We analyzed 3876 individuals aged ≥ 20 years who were confirmed with COVID-19 from January 1 to June 4, 2020 based on the Korea National Health Insurance Service (NHIS)-COVID-19 database and had undergone health examination by NHIS between 2015 and 2017. Multivariable Cox proportional hazard regression analyses were performed. RESULTS: Of total participants, the prevalence of MetS was 21.0% (n = 815). During 58.6 days of mean follow-up, 3.1 % (n = 120) of the participants died. Compared to individuals without MetS, COVID-19 patients with MetS had a significantly increased mortality risk after adjusting for confounders in total participants (hazard ratio [HR]: 1.68, 95 % confidence interval [CI]: 1.14-2.47) and women (HR: 2.41, 95 % CI: 1.17-4.96). A low high-density lipoprotein cholesterol level in total participants (HR: 1.63, 95 % CI: 1.12-2.37) and hyperglycemia in women (HR: 1.97, 95 % CI: 1.01-3.84) was associated with higher mortality risk. The mortality risk increased as the number of MetS components increased among total participants and women (P for trend = 0.009 and 0.016, respectively). In addition, MetS groups had higher mortality risk in aged ≥ 60 years (HR: 1.60, 95 % CI: 1.07-2.39), and never-smokers (2.08, 1.21-3.59). CONCLUSIONS: The presence of MetS and greater number of its components were associated with increased mortality risks particularly in female patients with COVID-19. Managing MetS may contribute to better outcomes of COVID-19.

Age at menopause and risk of heart failure and atrial fibrillation: a nationwide cohort study.

AIMS: This study aimed to examine the association of premature menopause and age at menopause with the risk of heart failure (HF) and atrial fibrillation (AF). METHODS AND RESULTS: A total of 1 401 175 postmenopausal women, who had undergone health examination provided by the Korean National Health Insurance Service, were included, and their reproductive histories were collected. Multivariable Cox proportional hazard models were performed to determine the hazard ratios (HRs) and 95% confidence intervals (CIs) of incident HF and AF, according to the history of premature menopause and age at menopause. At a mean follow-up of 9.1 years, there were 42 699 (3.0%) and 44 834 (3.2%) new cases of HF and AF, respectively. Women with history of premature menopause had an increased risk of HF (HR: 1.33, 95% CI: 1.26-1.40) and AF (HR: 1.09, 95% CI: 1.02-1.16), compared to women without the history. Compared with women aged ≥50 years at menopause, those aged 45-49, 40-44, and <40 years at menopause showed a significantly increased trend in HRs for the incident risk of both HF and AF (P for trend <0.001). The robustness of the results of a series of sensitivity analyses further strengthens the main findings. CONCLUSION: Our findings suggest that postmenopausal women with a history of premature menopause or early menopausal age may have an increased risk of HF and AF. These reproductive factors need to be considered for preventing the future risk of HF and AF.

Intake of mother's milk by very-low-birth-weight infants and variation in DNA methylation of genes involved in neurodevelopment at 5.5 years of age.

BACKGROUND: Mechanisms responsible for associations between intake of mother's milk in very-low-birth-weight (VLBW, <1500 g) infants and later neurodevelopment are poorly understood. It is proposed that early nutrition may affect neurodevelopmental pathways by altering gene expression through epigenetic modification. Variation in DNA methylation (DNAm) at cytosine-guanine dinucleotides (CpGs) is a commonly studied epigenetic modification. OBJECTIVES: We aimed to assess whether early mother's milk intake by VLBW infants is associated with variations in DNAm at 5.5 y, and whether these variations correlate with neurodevelopmental phenotypes. METHODS: This cohort study was a 5.5-y follow-up (2016-2018) of VLBW infants born in Ontario, Canada who participated in the Donor Milk for Improved Neurodevelopmental Outcomes trial. We performed an epigenome-wide association study (EWAS) to test whether percentage mother's milk (not including supplemental donor milk) during hospitalization was associated with DNAm in buccal cells during early childhood (n = 143; mean ± SD age: 5.7 ± 0.2 y; birth weight: 1008 ± 517 g). DNAm was assessed with the Illumina Infinium MethylationEPIC array at 814,583 CpGs. In secondary analyses, we tested associations between top-ranked CpGs and measures of early childhood neurodevelopment, e.g., total surface area of the cerebral cortex (n = 41, MRI) and Full-Scale IQ (n = 133, Wechsler Preschool and Primary Scale of Intelligence-IV). RESULTS: EWAS analysis demonstrated percentage mother's milk intake by VLBW infants during hospitalization was associated with DNAm at 2 CpGs, cg03744440 [myosin XVB (MYO15B)] and cg00851389 [metallothionein 1A (MT1A)], at 5.5 y (P < 9E-08). Gene set enrichment analysis indicated that top-ranked CpGs (P < 0.001) were annotated to genes enriched in neurodevelopmental biological processes. Corroborating these findings, DNAm at several top identified CpGs from the EWAS was associated with cortical surface area and IQ at 5.5 y (P < 0.05). CONCLUSIONS: In-hospital percentage mother's milk intake by VLBW infants was associated with variations in DNAm of neurodevelopmental genes at 5.5 y; some of these DNAm variations are associated with brain structure and IQ.This trial was registered at isrctn.com as ISRCTN35317141 and at clinicaltrials.gov as NCT02759809.

Visceral adiposity is associated with metabolic profiles predictive of type 2 diabetes and myocardial infarction.

Background: Visceral fat (VF) increases risk for cardiometabolic disease (CMD), the leading cause of morbidity and mortality. Variations in the circulating metabolome predict the risk for CMD but whether or not this is related to VF is unknown. Further, CMD is now also present in adolescents, and the relationships between VF, circulating metabolome, and CMD may vary between adolescents and adults. Methods: With an aim to add understanding to the metabolic variations in visceral obesity, we tested associations between VF, measured directly with magnetic resonance imaging, and 228 fasting serum metabolomic measures, quantified with nuclear magnetic resonance spectroscopy, in 507 adults (36-65 years) and 938 adolescents (12-18 years). We further utilized data from published studies to estimate similarities between VF and CMD-associated metabolic profiles. Results: Here we show that VF, independently of body mass index (BMI) or subcutaneous fat, is associated with triglyceride-rich lipoproteins, fatty acids, and inflammation in both adults and adolescents, whereas the associations with amino acids, glucose, and intermediary metabolites are significant in adults only. BMI-adjusted metabolomic profile of VF resembles those predicting type 2 diabetes in adults (R 2 = 0.88) and adolescents (R 2 = 0.70), and myocardial infarction in adults (R 2 = 0.59) and adolescents (R 2 = 0.40); this is not the case for ischemic stroke (adults: R 2 = 0.05, adolescents: R 2 = 0.08). Conclusions: Visceral adiposity is associated with metabolomic profiles predictive of type 2 diabetes and myocardial infarction even in normal-weight individuals and already in adolescence. Targeting factors contributing to the emergence and maintenance of these profiles might ameliorate their cumulative effects on cardiometabolic health.

Virtual Ontogeny of Cortical Growth Preceding Mental Illness.

BACKGROUND: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life. METHODS: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. RESULTS: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. CONCLUSIONS: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.

Circulating Metabolome and White Matter Hyperintensities in Women and Men.

BACKGROUND: White matter hyperintensities (WMH), identified on T2-weighted magnetic resonance images of the human brain as areas of enhanced brightness, are a major risk factor of stroke, dementia, and death. There are no large-scale studies testing associations between WMH and circulating metabolites. METHODS: We studied up to 9290 individuals (50.7% female, average age 61 years) from 15 populations of 8 community-based cohorts. WMH volume was quantified from T2-weighted or fluid-attenuated inversion recovery images or as hypointensities on T1-weighted images. Circulating metabolomic measures were assessed with mass spectrometry and nuclear magnetic resonance spectroscopy. Associations between WMH and metabolomic measures were tested by fitting linear regression models in the pooled sample and in sex-stratified and statin treatment-stratified subsamples. Our basic models were adjusted for age, sex, age×sex, and technical covariates, and our fully adjusted models were also adjusted for statin treatment, hypertension, type 2 diabetes, smoking, body mass index, and estimated glomerular filtration rate. Population-specific results were meta-analyzed using the fixed-effect inverse variance-weighted method. Associations with false discovery rate (FDR)-adjusted P values (PFDR)<0.05 were considered significant. RESULTS: In the meta-analysis of results from the basic models, we identified 30 metabolomic measures associated with WMH (PFDR<0.05), 7 of which remained significant in the fully adjusted models. The most significant association was with higher level of hydroxyphenylpyruvate in men (PFDR.full.adj=1.40×10-7) and in both the pooled sample (PFDR.full.adj=1.66×10-4) and statin-untreated (PFDR.full.adj=1.65×10-6) subsample. In men, hydroxyphenylpyruvate explained 3% to 14% of variance in WMH. In men and the pooled sample, WMH were also associated with lower levels of lysophosphatidylcholines and hydroxysphingomyelins and a larger diameter of low-density lipoprotein particles, likely arising from higher triglyceride to total lipids and lower cholesteryl ester to total lipids ratios within these particles. In women, the only significant association was with higher level of glucuronate (PFDR=0.047). CONCLUSIONS: Circulating metabolomic measures, including multiple lipid measures (eg, lysophosphatidylcholines, hydroxysphingomyelins, low-density lipoprotein size and composition) and nonlipid metabolites (eg, hydroxyphenylpyruvate, glucuronate), associate with WMH in a general population of middle-aged and older adults. Some metabolomic measures show marked sex specificities and explain a sizable proportion of WMH variance.

Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function.

We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP-CpG associations (methylation quantitative trait loci (meQTL), P < 10-14), including 467,915 meQTL that operate in trans. The meQTL are enriched for functionally relevant characteristics, including shared chromatin state, High-throuhgput chromosome conformation interaction, and association with gene expression, metabolic variation and clinical traits. We use molecular interaction and colocalization analyses to identify multiple nuclear regulatory pathways linking meQTL loci to phenotypic variation, including UBASH3B (body mass index), NFKBIE (rheumatoid arthritis), MGA (blood pressure) and COMMD7 (white cell counts). For rs6511961 , chromatin immunoprecipitation followed by sequencing (ChIP-seq) validates zinc finger protein (ZNF)333 as the likely trans acting effector protein. Finally, we used interaction analyses to identify population- and lineage-specific meQTL, including rs174548 in FADS1, with the strongest effect in CD8+ T cells, thus linking fatty acid metabolism with immune dysregulation and asthma. Our study advances understanding of the potential pathways linking genetic variation to human phenotype.

Genomic Studies Across the Lifespan Point to Early Mechanisms Determining Subcortical Volumes.

BACKGROUND: Subcortical brain structures play a key role in pathological processes of age-related neurodegenerative disorders. Mounting evidence also suggests that early-life factors may have an impact on the development of common late-life neurological diseases, including genetic factors that can influence both brain maturation and neurodegeneration. METHODS: Using large population-based brain imaging datasets across the lifespan (N ≤ 40,628), we aimed to 1) estimate the heritability of subcortical volumes in young (18-35 years), middle (35-65 years), and older (65+ years) age, and their genetic correlation across age groups; 2) identify whether genetic loci associated with subcortical volumes in older persons also show associations in early adulthood, and explore underlying genes using transcriptome-wide association studies; and 3) explore their association with neurological phenotypes. RESULTS: Heritability of subcortical volumes consistently decreased with increasing age. Genetic risk scores for smaller caudate nucleus, putamen, and hippocampus volume in older adults were associated with smaller volumes in young adults. Individually, 10 loci associated with subcortical volumes in older adults also showed associations in young adults. Within these loci, transcriptome-wide association studies showed that expression of several genes in brain tissues (especially MYLK2 and TUFM) was associated with subcortical volumes in both age groups. One risk variant for smaller caudate nucleus volume (TUFM locus) was associated with lower cognitive performance. Genetically predicted Alzheimer's disease was associated with smaller subcortical volumes in middle and older age. CONCLUSIONS: Our findings provide novel insights into the genetic determinants of subcortical volumes across the lifespan. More studies are needed to decipher the underlying biology and clinical impact.

The genetics of testosterone contributes to "femaleness/maleness" of cardiometabolic traits and type 2 diabetes.

The genetic architecture of testosterone is highly distinct between sexes. Moreover, obesity is associated with higher testosterone in females but lower testosterone in males. Here, we ask whether male-specific testosterone variants are associated with a male pattern of obesity and type 2 diabetes (T2D) in females, and vice versa. In the UK Biobank, we conducted sex-specific genome-wide association studies and computed polygenic scores for total (PGSTT) and bioavailable testosterone (PGSBT). We tested sex-congruent and sex-incongruent associations between sex-specific PGSTs and metabolic traits, as well as T2D diagnosis. Female-specific PGSBT was associated with an elevated cardiometabolic risk and probability of T2D, in both sexes. Male-specific PGSTT was associated with traits conferring a lower cardiometabolic risk and probability of T2D, in both sexes. We demonstrate the value in considering polygenic testosterone as sex-related continuous traits, in each sex.

SARS-CoV-2 Receptor ACE2 Gene Is Associated with Hypertension and Severity of COVID 19: Interaction with Sex, Obesity, and Smoking.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) has been identified as the entry receptor for coronaviruses into human cells, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). Since hypertension (HT) is a leading comorbidity in non-survivors of COVID-19, we tested for association between ACE2 gene and HT in interaction with specific pre-existing conditions known to be associated with COVID-19 severity. METHODS: Genetic analysis of ACE2 gene was conducted in French-Canadian (FC) and British populations. RESULTS: In FC individuals, the T allele of the single nucleotide polymorphism rs2074192 of ACE2 gene was a risk factor for HT in adult obese males [odds ratio (OR) = 1.39, 95% confidence interval (CI) 1.06-1.83)] and even more so in obese males who smoked (OR = 1.67, CI: 1.24-2.55), but not in lean males, non-smoker males or females. The T allele was significantly associated with severity of HT and with earlier penetrance of HT in obese smoking males. Significant interaction between the T allele and obesity was present in both sexes. The association of ACE2 (rs233575) genotype with blood pressure was also seen in adolescents but the interaction with obesity was present only in females. Several variants in ACE2 gene were found to be associated with HT in obese, smoking males in British individuals of the UK Biobank. In addition, we observed more severe outcomes to COVID-19 in association with ACE2 risk alleles in obese, smoking males. CONCLUSIONS: This is the first report that ACE2 variants are associated with earlier penetrance and more severe HT and with more severe outcomes of COVID-19 in obese smoking males.

A variant near DHCR24 associates with microstructural properties of white matter and peripheral lipid metabolism in adolescents.

Visceral adiposity has been associated with altered microstructural properties of white matter in adolescents. Previous evidence suggests that circulating phospholipid PC(16:0/2:0) may mediate this association. To investigate the underlying biology, we performed a genome-wide association study (GWAS) of the shared variance of visceral fat, PC(16:0/2:0), and white matter microstructure in 872 adolescents from the Saguenay Youth Study. We further studied the metabolomic profile of the GWAS-lead variant in 931 adolescents. Visceral fat and white matter microstructure were assessed with magnetic resonance imaging. Circulating metabolites were quantified with serum lipidomics and metabolomics. We identified a genome-wide significant association near DHCR24 (Seladin-1) encoding a cholesterol-synthesizing enzyme (rs588709, p = 3.6 × 10-8); rs588709 was also associated nominally with each of the three traits (white matter microstructure: p = 2.1 × 10-6, PC(16:0/2:0): p = 0.005, visceral fat: p = 0.010). We found that the metabolic profile associated with rs588709 resembled that of a TM6SF2 variant impacting very low-density lipoprotein (VLDL) secretion and was only partially similar to that of a HMGCR variant. This suggests that the effect of rs588709 on VLDL lipids may arise due to altered phospholipid rather than cholesterol metabolism. The rs588709 was also nominally associated with circulating concentrations of omega-3 fatty acids in interaction with visceral fat and PC(16:0/2:0), and these fatty acid measures showed robust associations with white matter microstructure. Overall, the present study provides evidence that the DHCR24 locus may link peripheral metabolism to brain microstructure, an association with implications for cognitive impairment.

Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.

IMPORTANCE: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood. OBJECTIVE: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244. MAIN OUTCOMES AND MEASURES: Interregional profiles of group difference in cortical thickness between cases and controls. RESULTS: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders. CONCLUSIONS AND RELEVANCE: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

Adiposity-related insulin resistance and thickness of the cerebral cortex in middle-aged adults.

The thickness of the cerebral cortex decreases with ageing. Recent research suggests that obesity and type 2 diabetes mellitus may accelerate this cortical thinning, and that obesity-related insulin resistance may be a shared mechanistic pathway. Ageing of the cerebral cortex demonstrates sex-specific trajectories, with a gradual shift towards accelerated thinning beginning in midlife. Here, we investigated whether adiposity-related insulin resistance is associated with lower thickness of the human cerebral cortex in a community-based sample of middle-aged adults. We studied 533 adult participants (36-65 years) from the Saguenay Youth Study. Adiposity was assessed with bioimpedance, and insulin resistance was evaluated from a fasting blood sample with the homeostatic model assessment of insulin resistance (HOMA-IR). Associations between adiposity-related insulin resistance (adiposity/IR) and cortical thickness were assessed with linear models, separately in males and females younger or older than 50 years. Potential biological underpinnings were investigated with virtual histology. Adiposity/IR was associated with lower cortical thickness in females older than 50 years but not in males or younger females. The strength of the association varied across the cerebral cortex, with regions of the lateral frontal and parietal cortices and the superior temporal cortex demonstrating most pronounced thinning. Based on virtual histology, adiposity/IR-related cortical thinning may involve neurones, astrocytes, oligodendrocytes and ependymal cells acting so that they lower the cortical potential for synaptogenesis, formation of dendritic spines, production of extracellular matrix and myelination. Adiposity-related insulin resistance is associated with lower cortical thickness in middle-aged women older than 50 years. This aspect of thinning may involve neuronal and glial cells in a way that lowers the capacity of the cerebral cortex for neuronal plasticity and maintenance of myelination.