Introduction:Recent genome-wide association studies have identified numerous single nucleotide polymorphisms (SNPs) associated with subcortical brain volumes. These studies have been undertaken in largely adult cohorts. In this work we explore the role of common genetic variability in fetal and perinatal brain development. We investigate how genetic variation, known to be associated with adult subcortical brain volume, affects the infant subcortical brain. Methods:We examine the influence of specific genetic loci and genome-wide polygenic scores on development of the fetal brain. Using a cohort of 208 term-born infants from the Developing Human Connectome Project, we ask whether eight SNPs, previously associated with adult subcortical brain volumes, show similar associations at birth. In addition, we compute genome-wide polygenic scores for the amygdala, brainstem, caudate, hippocampus, pallidum, putamen and thalamus and ask whether these scores are associated with the corresponding neonatal brain volumes. Results:We find that the association between SNP rs945270 and putamen volume, seen in adults, is present at birth (p = 3.67 × 10-3, β = 0.13, SE = 0.04). We also show that neonatal hippocampal, brainstem, putamen and thalamic volumes are all significantly associated with the genome-wide polygenic scores for their corresponding adult subcortical brain volume. Conclusions:Our results suggest that common genetic variation, important in shaping adult subcortical brain volume, also plays a significant role in fetal and perinatal brain development.

Increasing lines of evidence suggest cerebral overgrowth in autism spectrum disorder (ASD) children in early life, but few studies have examined the effect of ASD common genetic variants on brain volumes in a general paediatric population. This study examined the association between ASD polygenic risk score (PRS) and volumes of the frontal, temporal, parietal, occipital, fronto-temporal and parieto-occipital lobes in 273 term-born infants of European ancestry in the developing Human Connectome Project. ASD PRS was positively associated with frontal (β = 0.027, pFDR = 0.04) and fronto-temporal (β = 0.024, pFDR = 0.01) volumes, but negatively with parietal (β = −0.037, pFDR = 0.04) and parieto-occipital (β = −0.033, pFDR = 0.01) volumes. This preliminary result suggests the potential involvement of ASD common genetic variants in early structural variations linked to ASD.

Genome-wide association studies (GWAS) have characterized the contribution of common variants to breast cancer (BC) risk in populations of European ancestry, however GWAS have not been reported in resident African populations. This GWAS included 2485 resident African BC cases and 1101 population matched controls. Two risk loci were identified, located between UNC13C and RAB27A on chromosome 15 (rs7181788, p = 1.01 × 10 −08 ) and in USP22 on chromosome 17 (rs899342, p = 4.62 × 10 −08 ). Several genome-wide significant signals were also detected in hormone receptor subtype analysis. The novel loci did not replicate in BC GWAS data from populations of West Africa ancestry suggesting genetic heterogeneity in different African populations, but further validation of these findings is needed. A European ancestry derived polygenic risk model for BC explained only 0.79% of variance in our data. Larger studies in pan-African populations are needed to further define the genetic contribution to BC risk.

Depression is a risk factor for the later development of Alzheimer’s disease (AD), but evidence for the genetic relationship is mixed. Assessing depression symptom-specific genetic associations may better clarify this relationship. To address this, we conducted genome-wide meta-analysis (a genome-wide association study, GWAS) of the nine depression symptom items, plus their sum score, on the Patient Health Questionnaire (PHQ-9) (GWAS-equivalent N: 224,535–308,421) using data from UK Biobank, the GLAD study and PROTECT, identifying 37 genomic risk loci. Using six AD GWASs with varying proportions of clinical and proxy (family history) case ascertainment, we identified 20 significant genetic correlations with depression/depression symptoms. However, only one of these was identified with a clinical AD GWAS. Local genetic correlations were detected in 14 regions. No statistical colocalization was identified in these regions. However, the region of the transmembrane protein 106B gene (TMEM106B) showed colocalization between multiple depression phenotypes and both clinical-only and clinical + proxy AD. Mendelian randomization and polygenic risk score analyses did not yield significant results after multiple testing correction in either direction. Our findings do not demonstrate a causal role of depression/depression symptoms on AD and suggest that previous evidence of genetic overlap between depression and AD may be driven by the inclusion of family history-based proxy cases/controls. However, colocalization at TMEM106B warrants further investigation. Using genome-wide meta-analyses of clinical measures of depression and biobank data, the authors investigate symptom-specific genetic associations between depression and subsequent risk for Alzheimer’s disease, finding an absence of a putative genetic overlap between disorders.

Increasing lines of evidence suggest white matter (WM) structural changes associated with autism can be detected in the first year of life. Despite the condition having high heritability, the relationship between autism common genetic variants and WM changes during this period remains unclear. By employing advanced regional and whole-brain fixel-based analysis, the current study investigated the association between autism polygenic scores (PS) and WM microscopic fibre density and macrostructural morphology in 221 term-born infants of European ancestry from the developing Human Connectome Project. The results suggest greater tract mean fibre-bundle cross-section of the left superior corona radiata is associated with higher autism PS. Subsequent exploratory enrichment analysis revealed that the autism risk single nucleotide polymorphisms most associated with the imaging phenotype may have roles in neuronal cellular components. Together, these findings suggest a possible link between autism common variants and early WM development.

Rapid and accessible testing was paramount in the management of the COVID-19 pandemic. Our university established KCL TEST: a SARS-CoV-2 asymptomatic testing programme that enabled sensitive and accessible PCR testing of SARS-CoV-2 RNA in saliva. Here, we describe our learnings and provide our blueprint for launching diagnostic laboratories, particularly in low-resource settings. Between December 2020 and July 2022, we performed 158277 PCRs for our staff, students, and their household contacts, free of charge. Our average turnaround time was 16 h and 37 min from user registration to result delivery. KCL TEST combined open-source automation and in-house non-commercial reagents, which allows for rapid implementation and repurposing. Importantly, our data parallel those of the UK Office for National Statistics, though we detected a lower positive rate and virtually no delta wave. Our observations strongly support regular asymptomatic community testing as an important measure for decreasing outbreaks and providing safe working spaces. Universities can therefore provide agile, resilient, and accurate testing that reflects the infection rate and trend of the general population. Our findings call for the early integration of academic institutions in pandemic preparedness, with capabilities to rapidly deploy highly skilled staff, as well as develop, test, and accommodate efficient low-cost pipelines.

Repeat expansions in the C9orf72 gene are the most common genetic cause of (ALS) and frontotemporal dementia (FTD). Like other genetic forms of neurodegeneration, pinpointing the precise mechanism(s) by which this mutation leads to neuronal death remains elusive, and this lack of knowledge hampers the development of therapy for C9orf72-related disease. We used an agnostic approach based on genomic data (n = 41,273 ALS and healthy samples, and n = 1,516 C9orf72 carriers) to overcome these bottlenecks. Our drug-repurposing screen, based on gene- and expression-pattern matching and information about the genetic variants influencing onset age among C9orf72 carriers, identified acamprosate, a γ-aminobutyric acid analog, as a potentially repurposable treatment for patients carrying C9orf72 repeat expansions. We validated its neuroprotective effect in cell models and showed comparable efficacy to riluzole, the current standard of care. Our work highlights the potential value of genomics in repurposing drugs in situations where the underlying pathomechanisms are inherently complex. VIDEO ABSTRACT.

BackgroundPalmoplantar pustulosis (PPP) is an inflammatory skin disorder that mostly affects smokers and manifests with painful pustular eruptions on the palms and soles. While the disease can present with concurrent plaque psoriasis, TNF and IL-17/IL-23 inhibitors show limited efficacy. There is therefore a pressing need to uncover PPP disease drivers and therapeutic targets.ObjectivesTo identify genetic determinants of PPP and investigate whether cigarette smoking contributes to disease pathogenesis.MethodsWe performed a genome-wide association meta-analysis of three North-European cohorts (n=1,456 PPP cases and 402,050 controls). We then used the scGWAS program to investigate the cell-type specificity of the association signals. We also undertook genetic correlation analyses to examine the similarities between PPP and other immune-mediated diseases. Finally, we applied Mendelian randomization to analyze the causal relationship between cigarette smoking and PPP.ResultsWe found that PPP is not associated with the main genetic determinants of plaque psoriasis. Conversely, we identified genome-wide significant associations with the FCGR3A/FCGR3B and CCHCR1 loci. We also observed 13 suggestive (P<5X10-6) susceptibility regions, including the IL4/IL13 interval. Accordingly, we demonstrated a significant genetic correlation between PPP and Th2-mediated diseases like atopic dermatitis and ulcerative colitis. We also found that genes mapping to PPP-associated intervals were preferentially expressed in dendritic cells and often implicated in T-cell activation pathways. Finally, we undertook a Mendelian randomization analysis, which supported a causal role of cigarette smoking in PPP.ConclusionsThe first genome-wide association study of PPP points to a pathogenic role for deregulated Th2 responses and cigarette smoking.

Increasing lines of evidence suggest abnormalities in motor related brain regions and motor function may be pervasive in autism spectrum disorder (ASD) as early as infancy, but the effect of ASD common variants on these phenotypes remains poorly understood. Recent studies in general paediatric populations found higher ASD polygenic score was associated with lower early motor developmental outcome in infants (Takahashi et al., 2020; Serdarevic et al., 2020), but increased connectivity in motor areas in 3-14-year-old children (Khundrakpam et al., 2020). Concurrently, increased radiate white matter volume within primary motor region was also related to poorer motor function in 8–12-year-old ASD children (Mostofsky et al., 2007). Corticospinal tract (CST), originating chiefly from the primary motor cortex, is the principal motor pathway for voluntary movements; abnormal white matter radial and mean diffusivity of which has been associated with ASD in children and adolescent (Carper et al., 2015). Therefore, the current work aimed to examine the effect of ASD common variants on CST morphology in infants at birth using fixel-based analysis framework. Diffusion imaging and genetic data were analysed for 221 term-born infants (at least 37 weeks of completed gestation) of European ancestry in the developing Human Connectome Project (dHCP) (Edwards et al., 2022). Optimised neonatal multi-shell high angular resolution diffusion imaging acquisition protocol and the following denoising, Gibbs ringing suppression, motion and image distortion correction process were employed according to the dHCP pipeline. Individual fixel (individual fiber population within a voxel) orientation distribution maps generated using MRtrix3 were normalized and registered to a common 40-week anatomical template. Tractography of the CST was performed on the common template using probabilistic algorithm with 10 million seeds. CST fixel-wise measure of fiber density (FD), fiber cross-section (FC) and fiber density cross-section (FDC) were calculated for each individual. Here, FD measures the local differences in intra-axonal volume, FC is the difference in intraxonal volume manifested in the number of voxels the fiber bundle occupies, and FDC is the multiplication of the two values. Polygenic scores (PS), defined as the sum of the number of the risk alleles weighted by the strength of their association with ASD derived from the summary statistics provided by the latest genome-wide association study (Grove et al. 2019), were estimated at 10 different p-value thresholds using PRSice-2 (Choi and O'Reilly 2019). Fixel-wise linear regression was then fitted to estimate the association between each PS and fixel-based fiber measures, adjusting for ages at birth and at scans, first 3 ancestry principal components (PCs), sex and total brain volume (only for FC and FDC). Using spectrum decomposition method to account for correlated PS (Li and Ji, 2005), a fixel was considered significant if the family-wise error pFWE -value was < 0.008. Log(FC) and FDC, but not FD of fibers within the left CST were statistically associated with ASD PS PT=0.01 (pFWE < 0.008), where higher PS was associated with increased intra-axonal volume at macrostructural, but not microstructural level. This is the first study examining CST in relation to ASD PS in a general population at birth. This preliminary result warrants further examination of clinical utility of motor function as early phenotype of ASD.

AbstractDepression is a risk factor for Alzheimer’s disease (AD), but evidence for their genetic relationship is mixed. Assessing depression symptom specific genetic associations may better clarify this relationship.Using data from the UK Biobank, the GLAD Study and PROTECT, we performed the largest genome-wide meta-analyses (GWAS) of the nine depression symptom items, plus their sum score, on the Patient Health Questionnaire (PHQ-9) (GWAS equivalent N: 224,535—308,421). We assessed global/local genetic correlations and statistical colocalisation between depression phenotypes and AD across six AD GWAS with varying proportions of clinical and proxy (family history) case ascertainment. We assessed bi-directional causal associations using Mendelian randomisation (MR) and the predictiveness of depression phenotype polygenic risk scores (PRS) for AD case/control status in three clinical AD cohorts.Our GWAS meta-analyses identified 37 genomic risk loci across the ten depression symptom phenotypes. Of the 72 global genetic correlation tests conducted between depression/depression symptoms and AD, 20 were significant at pFDR≤ 0.05. Only one significant genetic correlation was identified with AD GWAS containing clinical-only cases. Colocalisation was not identified at loci contains local genetic correlation but was identified in the region of transmembrane protein 106B (TMEM106B) between multiple depression phenotypes and both clinical-only and clinical+proxy AD. MR and PRS analyses did not yield statistically significant results.Our findings do not demonstrate a causal role of depression/depression symptoms on AD and suggest that previous evidence of their genetic overlap may be driven by the inclusion of proxy cases/controls. However, the identification of colocalisation at TMEM106B warrants further investigation.

Increasing lines of evidence suggest deviations from the normal early developmental trajectory could give rise to the onset of schizophrenia during adolescence and young adulthood, but few studies have investigated brain imaging changes associated with schizophrenia common variants in neonates. This study compared the brain volumes of both grey and white matter regions with schizophrenia polygenic risk scores (PRS) for 207 healthy term-born infants of European ancestry. Linear regression was used to estimate the relationship between PRS and brain volumes, with gestational age at birth, postmenstrual age at scan, ancestral principal components, sex and intracranial volumes as covariates. The schizophrenia PRS were negatively associated with the grey ( β = −0.08, p = 4.2 × 10 −3 ) and white ( β = −0.13, p = 9.4 × 10 −3 ) matter superior temporal gyrus volumes, white frontal lobe volume ( β = −0.09, p = 1.5 × 10 −3 ) and the total white matter volume ( β = −0.062, p = 1.66 × 10 −2 ). This result also remained robust when incorporating individuals of Asian ancestry. Explorative functional analysis of the schizophrenia risk variants associated with the right frontal lobe white matter volume found enrichment in neurodevelopmental pathways. This preliminary result suggests possible involvement of schizophrenia risk genes in early brain growth, and potential early life structural alterations long before the average age of onset of the disease.

Esophageal squamous cell carcinoma (ESCC) has a high disease burden in sub-Saharan Africa and has a very poor prognosis. Genomewide association studies (GWASs) of ESCC in predominantly East Asian populations indicate a substantial genetic contribution to its etiology, but no genome-wide studies have been done in populations of African ancestry. Here, we report a GWAS in 1,686 African individuals with ESCC and 3,217 population-matched control individuals to investigate its genetic etiology. We identified a genome-wide-significant risk locus on chromosome 9 upstream of FAM120A (rs12379660, p = 4.58 3 10-8, odds ratio = 1.28, 95% confidence interval = 1.22-1.34), as well as a potential African-specific risk locus on chromosome 2 (rs142741123, p = 5.49 3 10-8) within MYO1B. FAM120A is a component of oxidative stress-induced survival signals, and the associated variants at the FAM120A locus co-localized with highly significant cis-eQTLs in FAM120AOS in both esophageal mucosa and esophageal muscularis tissue. A trans-ethnic meta-analysis was then performed with the African ESCC study and a Chinese ESCC study in a combined total of 3,699 ESCC-affected individuals and 5,918 control individuals, which identified three genome-wide-significant loci on chromosome 9 at FAM120A (rs12379660, pmeta = 9.36 3 10-10), chromosome 10 at PLCE1 (rs7099485, pmeta = 1.48 3 10-8), and chromosome 22 at CHEK2 (rs1033667, pmeta = 1.47 3 10-9). This indicates the existence of both shared and distinct genetic risk loci for ESCC in African and Asian populations. Our GWAS of ESCC conducted in a population of African ancestry indicates a substantial genetic contribution to ESCC risk in Africa.

Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To move towards a saturation map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 45 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2 , CPVL and POU2F3 ). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

1.AbstractRecent genome-wide association studies have identified numerous single nucleotide polymorphisms (SNPs) associated with subcortical brain volumes. These studies have been undertaken in largely adult cohorts. To better understand the role of genetic variability in foetal and perinatal brain development, we investigate how common genetic variation affects subcortical brain development in a cohort of 208 term-born infants from the Developing Human Connectome Project.We examine six SNPs, that have shown robust associations with subcortical brain volumes in adult studies and ask if these associations exist at birth. We then investigate whether genome-wide polygenic scores (GPSs) for adult subcortical brain volumes are predictive of the corresponding neonatal brain volume. Finally, we explore the relationship between GPSs for psychiatric disorders and subcortical brain volume at birth.We find the association between SNP rs945270 and putamen volume, seen in adults, is present at birth (p=3.67×10-3, β=0.13, SE=0.04). The associations between SNP rs61921502 and hippocampal volume and SNP rs11111090 and brainstem volume are also nominally present in our neonatal cohort. We show that neonatal hippocampal, brainstem, putamen and thalamic volume are all significantly associated with the GPSs for their corresponding volume in adults. Finally, we find that GPSs for five psychiatric disorders and a cross-disorder score are not significantly predictive of subcortical brain volumes or total brain volume at birth. Our results indicate that SNPs important in shaping adult subcortical brain volume are also significant in foetal and perinatal brain development.Key PointsWe show that the association between the single nucleotide polymorphism, rs945270 and putamen volume, seen in adults, is present in neonates.We show that neonatal hippocampal, putamen, brainstem and thalamic volumes are all significantly predicted by the genome-wide polygenic scores for corresponding adult brain volumes.We do not find any robust association between genome-wide polygenic scores for psychiatric disorders and neonatal brain volume although we observe several nominal associations.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.