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Genome Biology Jun 2023The pathophysiological causes of kidney disease are not fully understood. Here we show that the integration of genome-wide genetic, transcriptomic, and proteomic...
BACKGROUND
The pathophysiological causes of kidney disease are not fully understood. Here we show that the integration of genome-wide genetic, transcriptomic, and proteomic association studies can nominate causal determinants of kidney function and damage.
RESULTS
Through transcriptome-wide association studies (TWAS) in kidney cortex, kidney tubule, liver, and whole blood and proteome-wide association studies (PWAS) in plasma, we assess for effects of 12,893 genes and 1342 proteins on kidney filtration (glomerular filtration rate (GFR) estimated by creatinine; GFR estimated by cystatin C; and blood urea nitrogen) and kidney damage (albuminuria). We find 1561 associations distributed among 260 genomic regions that are supported as putatively causal. We then prioritize 153 of these genomic regions using additional colocalization analyses. Our genome-wide findings are supported by existing knowledge (animal models for MANBA, DACH1, SH3YL1, INHBB), exceed the underlying GWAS signals (28 region-trait combinations without significant GWAS hit), identify independent gene/protein-trait associations within the same genomic region (INHBC, SPRYD4), nominate tissues underlying the associations (tubule expression of NRBP1), and distinguish markers of kidney filtration from those with a role in creatinine and cystatin C metabolism. Furthermore, we follow up on members of the TGF-beta superfamily of proteins and find a prognostic value of INHBC for kidney disease progression even after adjustment for measured glomerular filtration rate (GFR).
CONCLUSION
In summary, this study combines multimodal, genome-wide association studies to generate a catalog of putatively causal target genes and proteins relevant to kidney function and damage which can guide follow-up studies in physiology, basic science, and clinical medicine.
Topics: Animals; Renal Insufficiency, Chronic; Cystatin C; Proteome; Transcriptome; Creatinine; Genome-Wide Association Study; Proteomics; Kidney
PubMed: 37365616
DOI: 10.1186/s13059-023-02993-y -
Nature Oct 2023The ever-growing compendium of genetic variants associated with human pathologies demands new methods to study genotype-phenotype relationships in complex tissues in a...
The ever-growing compendium of genetic variants associated with human pathologies demands new methods to study genotype-phenotype relationships in complex tissues in a high-throughput manner. Here we introduce adeno-associated virus (AAV)-mediated direct in vivo single-cell CRISPR screening, termed AAV-Perturb-seq, a tuneable and broadly applicable method for transcriptional linkage analysis as well as high-throughput and high-resolution phenotyping of genetic perturbations in vivo. We applied AAV-Perturb-seq using gene editing and transcriptional inhibition to systematically dissect the phenotypic landscape underlying 22q11.2 deletion syndrome genes in the adult mouse brain prefrontal cortex. We identified three 22q11.2-linked genes involved in known and previously undescribed pathways orchestrating neuronal functions in vivo that explain approximately 40% of the transcriptional changes observed in a 22q11.2-deletion mouse model. Our findings suggest that the 22q11.2-deletion syndrome transcriptional phenotype found in mature neurons may in part be due to the broad dysregulation of a class of genes associated with disease susceptibility that are important for dysfunctional RNA processing and synaptic function. Our study establishes a flexible and scalable direct in vivo method to facilitate causal understanding of biological and disease mechanisms with potential applications to identify genetic interventions and therapeutic targets for treating disease.
Topics: Animals; Humans; Mice; Dependovirus; Gene Editing; Genetic Association Studies; Neurons; Phenotype; Prefrontal Cortex; Transcription, Genetic; Single-Cell Analysis; CRISPR-Cas Systems; DiGeorge Syndrome; Disease Models, Animal; RNA Processing, Post-Transcriptional; Synapses; Genetic Predisposition to Disease
PubMed: 37730998
DOI: 10.1038/s41586-023-06570-y -
BMJ (Clinical Research Ed.) Aug 2023To investigate the associations between exposure to antenatal corticosteroids and serious infection in children during the first three, six, and 12 months of life.
OBJECTIVE
To investigate the associations between exposure to antenatal corticosteroids and serious infection in children during the first three, six, and 12 months of life.
DESIGN
Nationwide cohort study.
SETTING
National Health Insurance Research Database, Birth Reporting Database, and Maternal and Child Health Database, 1 January 2008 to 31 December 2019, to identify all pregnant individuals and their offspring in Taiwan.
PARTICIPANTS
1 960 545 pairs of pregnant individuals and their singleton offspring. 45 232 children were exposed and 1 915 313 were not exposed to antenatal corticosteroids.
MAIN OUTCOME MEASURES
Incidence rates were estimated for overall serious infection, sepsis, pneumonia, acute gastroenteritis, pyelonephritis, meningitis or encephalitis, cellulitis or soft tissue infection, septic arthritis or osteomyelitis, and endocarditis during the first three, six, and 12 months of life in children exposed versus those not exposed to antenatal corticosteroids. Cox proportional hazards models were performed to quantify adjusted hazard ratios with 95% confidence intervals for each study outcome.
RESULTS
The study cohort was 1 960 545 singleton children: 45 232 children were exposed to one course of antenatal corticosteroids and 1 915 313 children were not exposed to antenatal corticosteroids. The adjusted hazard ratios for overall serious infection, sepsis, pneumonia, and acute gastroenteritis among children exposed to antenatal corticosteroids were significantly higher than those not exposed to antenatal corticosteroids during the first six months of life (adjusted hazard ratio 1.32, 95% confidence interval 1.18 to 1.47, P<0.001, for overall serious infection; 1.74, 1.16 to 2.61, P=0.01, for sepsis; 1.39, 1.17 to 1.65, P<0.001, for pneumonia; and 1.35, 1.10 to 1.65, P<0.001, for acute gastroenteritis).Similarly, the adjusted hazard ratios for overall serious infection (P<0.001), sepsis (P=0.02), pneumonia (P<0.001), and acute gastroenteritis (P<0.001) were significantly higher from birth to 12 months of life. In the sibling matched cohort, the results were comparable with those observed in the whole cohort, with a significantly increased risk of sepsis in the first six (P=0.01) and 12 (P=0.04) months of life.
CONCLUSIONS
This nationwide cohort study found that children exposed to one course of antenatal corticosteroids were significantly more likely to have an increased risk of serious infection during the first 12 months of life. These findings suggest that before starting treatment, the long term risks of rare but serious infection associated with antenatal corticosteroids should be carefully weighed against the benefits in the perinatal period.
Topics: Humans; Pregnancy; Child; Female; Cohort Studies; Adrenal Cortex Hormones; Taiwan; Premature Birth
PubMed: 37532264
DOI: 10.1136/bmj-2023-075835 -
Journal of Affective Disorders Aug 2023The consumption of ultra-processed foods and drinks (UPF) has been associated with depression and inflammation and preclinical studies showed that some UPF components...
BACKGROUND
The consumption of ultra-processed foods and drinks (UPF) has been associated with depression and inflammation and preclinical studies showed that some UPF components disrupt the amygdala-hippocampal complex. We combine diet, clinical and brain imaging data to investigate the relationship between the UPF consumption, depressive symptoms, and brain volumes in humans, considering interactions with obesity, and the mediation effect of inflammation biomarkers.
METHODS
One-hundred fifty-two adults underwent diet, depressive symptoms, anatomic magnetic resonance imaging assessments and laboratory tests. Relationships between the % of UPF consumption (in grams) of the total diet, depressive symptoms, and gray matter brain volumes were explored using several adjusted regression models, and in interaction with the presence of obesity. Whether inflammatory biomarkers (i.e., white blood cell count, lipopolysaccharide-binding protein, c-reactive protein) mediate the previous associations was investigated using R mediation package.
RESULTS
High UPF consumption was associated with higher depressive symptoms in all participants (β = 0.178, CI = 0.008-0.261) and in those with obesity (β = 0.214, CI = -0.004-0.333). Higher consumption was also associated with lower volumes in the posterior cingulate cortex and the left amygdala, which in the participants with obesity also encompassed the left ventral putamen and the dorsal frontal cortex. White blood count levels mediated the association between UPF consumption and depressive symptoms (p = 0.022).
LIMITATIONS
The present study precludes any causal conclusions.
CONCLUSIONS
UPF consumption is associated with depressive symptoms and lower volumes within the mesocorticolimbic brain network implicated in reward processes and conflict monitoring. Associations were partially dependent on obesity and white blood cell count.
Topics: Adult; Humans; Food, Processed; Depression; Fast Foods; Diet; Obesity; Inflammation; Biomarkers
PubMed: 37207947
DOI: 10.1016/j.jad.2023.05.009 -
Bone Research Jul 2023In this study, we aimed to investigate the causal associations of brain structure with bone mineral density (BMD). Based on the genome-wide association study (GWAS)...
In this study, we aimed to investigate the causal associations of brain structure with bone mineral density (BMD). Based on the genome-wide association study (GWAS) summary statistics of 1 325 brain imaging-derived phenotypes (BIDPs) of brain structure from the UK Biobank and GWAS summary datasets of 5 BMD locations, including the total body, femoral neck, lumbar spine, forearm, and heel from the GEFOS Consortium, linkage disequilibrium score regression (LDSC) was conducted to determine the genetic correlations, and Mendelian randomization (MR) was then performed to explore the causal relationship between the BIDPs and BMD. Several sensitivity analyses were performed to verify the strength and stability of the present MR outcomes. To increase confidence in our findings, we also performed confirmatory MR between BIDPs and osteoporosis. LDSC revealed that 1.93% of BIDPs, with a false discovery rate (FDR) < 0.01, were genetically correlated with BMD. Additionally, we observed that 1.31% of BIDPs exhibited a significant causal relationship with BMD (FDR < 0.01) through MR. Both the LDSC and MR results demonstrated that the BIDPs "Volume of normalized brain," "Volume of gray matter in Left Inferior Frontal Gyrus, pars opercularis," "Volume of Estimated Total Intra Cranial" and "Volume-ratio of brain segmentation/estimated total intracranial" had strong associations with BMD. Interestingly, our results showed that more left BIDPs were causally associated with BMD, especially within and around the left frontal region. In conclusion, a part of the brain structure causally influences BMD, which may provide important perspectives for the prevention of osteoporosis and offer valuable insights for further research on the brain-bone axis.
Topics: Humans; Bone Density; Genome-Wide Association Study; Correlation of Data; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Osteoporosis; Femur Neck; Prefrontal Cortex
PubMed: 37474577
DOI: 10.1038/s41413-023-00270-z -
Journal of Neurophysiology Jun 2024The striatum receives projections from multiple regions of the cerebral cortex consistent with the role of the basal ganglia in diverse motor, affective, and cognitive...
The striatum receives projections from multiple regions of the cerebral cortex consistent with the role of the basal ganglia in diverse motor, affective, and cognitive functions. Within the striatum, the caudate receives projections from association cortex, including multiple distinct regions of prefrontal cortex. Building on recent insights about the details of how juxtaposed cortical networks are specialized for distinct aspects of higher-order cognition, we revisited caudate organization using within-individual precision neuroimaging initially in two intensively scanned individuals (each scanned 31 times). Results revealed that the caudate has side-by-side regions that are coupled to at least five distinct distributed association networks, paralleling the organization observed in the cerebral cortex. We refer to these spatial groupings of regions as striatal association megaclusters. Correlation maps from closely juxtaposed seed regions placed within the megaclusters recapitulated the five distinct cortical networks, including their multiple spatially distributed regions. Striatal association megaclusters were explored in 15 additional participants (each scanned at least 8 times), finding that their presence generalizes to new participants. Analysis of the laterality of the regions within the megaclusters further revealed that they possess asymmetries paralleling their cortical counterparts. For example, caudate regions linked to the language network were left lateralized. These results extend the general notion of parallel specialized basal ganglia circuits with the additional discovery that, even within the caudate, there is fine-grained separation of multiple distinct higher-order networks that reflects the organization and lateralization found in the cerebral cortex. An individualized precision neuroimaging approach reveals juxtaposed zones of the caudate that are coupled with five distinct networks in association cortex. The organization of these caudate zones recapitulates organization observed in the cerebral cortex and extends the notion of specialized basal ganglia circuits.
Topics: Humans; Male; Adult; Female; Caudate Nucleus; Corpus Striatum; Cerebral Cortex; Magnetic Resonance Imaging; Neural Pathways; Young Adult; Nerve Net; Middle Aged
PubMed: 38505898
DOI: 10.1152/jn.00387.2023