Effects of urban living environments on mental health in adults

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(6), P. 1456 - 1467

Published: June 1, 2023

Abstract Urban-living individuals are exposed to many environmental factors that may combine and interact influence mental health. While individual of an urban environment have been investigated in isolation, no attempt has made model how complex, real-life exposure living the city relates brain health, this is moderated by genetic factors. Using data 156,075 participants from UK Biobank, we carried out sparse canonical correlation analyses investigate relationships between environments psychiatric symptoms. We found profile social deprivation, air pollution, street network land-use density was positively correlated with affective symptom group ( r = 0.22, P perm < 0.001), mediated volume differences consistent reward processing, genes enriched for stress response, including CRHR1 , explaining 2.01% variance differences. Protective such as greenness generous destination accessibility were negatively anxiety 0.10, regions necessary emotion regulation EXD3 1.65% variance. The third emotional instability 0.03, 0.001). Our findings suggest different profiles specific groups through distinct neurobiological pathways.

Language: Английский

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Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson’s disease

Cell Reports, Journal Year: 2025, Volume and Issue: unknown, P. 115355 - 115355

Published: March 1, 2025

Highlights•ITSN1 haploinsufficiency confers a ∼10-fold increased risk of Parkinson's disease (PD)•Effect size surpasses other well-established loci, including GBA1 and LRRK2•In vivo in vitro studies suggest an interaction between ITSN1 α-synuclein•Findings implicate synaptic vesicle trafficking dysfunction PD pathogenesisSummaryDespite its significant heritability, the genetic basis (PD) remains incompletely understood. Here, analyzing whole-genome sequence data from 3,809 cases 247,101 controls UK Biobank, we discover that protein-truncating variants confer substantially (p = 6.1 × 10−7; odds ratio [95% confidence interval] 10.5 [5.2, 21.3]). We replicate this association three independent datasets totaling 8,407 413,432 (combined p 4.5 10−12). Notably, has also been associated with autism spectrum disorder, suggesting variable penetrance/expressivity. In Drosophila, find loss ortholog Dap160 exacerbates α-synuclein-induced neuronal toxicity motor deficits, assays further physical α-synuclein. These results firmly establish as gene effect exceeding previously established vesicular pathogenesis, potentially open new avenues for therapeutic development.Graphical abstract

Language: Английский

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Human leukocyte antigen super-locus: nexus of genomic supergenes, SNPs, indels, transcripts, and haplotypes

Human Genome Variation, Journal Year: 2022, Volume and Issue: 9(1)

Published: Dec. 21, 2022

The human Major Histocompatibility Complex (MHC) or Human Leukocyte Antigen (HLA) super-locus is a highly polymorphic genomic region that encodes more than 140 coding genes including the transplantation and immune regulatory molecules. It receives special attention for genetic investigation because of its important role in regulation innate adaptive responses strong association with numerous infectious and/or autoimmune diseases. In recent years, MHC genotyping haplotyping using Sanger sequencing next-generation (NGS) methods have produced many hundreds sequences HLA comparative studies architecture diversity between same different haplotypes. this issue on 'The Current Landscape Genomics Genetics', we provide short review some analytical developments used to investigate SNP polymorphisms, structural variants (indels), transcription haplotypes super-locus. This highlights importance reference cell-lines, population studies, NGS improve update our understanding mechanisms, architectural structures combinations alleles (SNPs indels) better define characterise their various phenotypes

Language: Английский

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Impact of population structure in the estimation of recent historical effective population size by the software GONE

Genetics Selection Evolution, Journal Year: 2023, Volume and Issue: 55(1)

Published: Dec. 4, 2023

Effective population size (Ne) is a crucial parameter in conservation genetics and animal breeding. A recent method, implemented by the software GONE, has been shown to be rather accurate estimating historical changes Ne from single sample of individuals. However, GONE estimations assume that being studied remained isolated for period time, is, without migration or confluence other populations. If this occurs, estimates can heavily biased. In paper, we evaluate impact admixture on provided through series computer simulations considering several scenarios: (a) mixture two more ancestral populations; (b) subpopulations continuously exchange individuals migration; (c) populations receiving migrants large source; (d) with balanced systems chromosomal inversions, which also generate genetic structure.Our results indicate may substantially biased when there were previously separated long time. Similarly, biases occur rate continued between low, inversions are present at high frequencies. some due structuring eliminated conducting structure analyses restricting estimation differentiated groups. addition, disregarding genomic regions involved remove Ne.Different kinds deviations isolation panmixia Ne. Therefore, past demography could benefit performing beforehand, mitigating these estimates.

Language: Английский

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Chromosomal inversion polymorphisms shape human brain morphology

Cell Reports, Journal Year: 2023, Volume and Issue: 42(8), P. 112896 - 112896

Published: July 27, 2023

The impact of chromosomal inversions on human brain morphology remains underexplored. We studied 35 common classified from genotypes 33,018 adults with European ancestry. at 2p22.3, 16p11.2, and 17q21.31 reach genome-wide significance, followed by 8p23.1 6p21.33, in their association cortical subcortical morphology. 17q21.31, 8p23.1, 16p11.2 regions comprise the LRRC37, OR7E, NPIP duplicated gene families. find MAPT inversion region, known for harboring neurological risk, to be most salient locus among variants shaping patterning cortex. Overall, we observe inverted orientations decreasing size, exception that 2p22.3 is associated increased volume motor These significant are genomic hotspots neuropsychiatric loci. Our findings generalizable 3,472 children demonstrate as essential genetic variation understand phenotypes.

Language: Английский

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Genomic architecture of supergenes: connecting form and function

Philosophical Transactions of the Royal Society B Biological Sciences, Journal Year: 2022, Volume and Issue: 377(1856)

Published: June 13, 2022

Supergenes are tightly linked sets of loci that inherited together and control complex phenotypes. While classical supergenes-governing traits such as wing patterns in Heliconius butterflies or heterostyly Primula-have been studied since the Modern Synthesis, we still understand very little about how they evolve persist nature. The genetic architecture supergenes is a critical factor affecting their evolutionary fate, it can change key parameters recombination rate effective population size, potentially redirecting molecular evolution supergene addition to surrounding genomic region. To evolution, must link with processes. This now becoming possible recent advances sequencing technology powerful forward computer simulations. present theme issue brings theoretical empirical papers, well opinion synthesis which showcase architectural diversity connect this processes polymorphism maintenance mutation accumulation. Here, summarize those insights highlight new ideas methods illuminate path for study article part 'Genomic supergenes: causes consequences'.

Language: Английский

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Genomic architecture and functional effects of potential human inversion supergenes

Philosophical Transactions of the Royal Society B Biological Sciences, Journal Year: 2022, Volume and Issue: 377(1856)

Published: June 13, 2022

Supergenes are involved in adaptation multiple organisms, but they little known humans. Genomic inversions the most common mechanism of supergene generation and maintenance. Here, we review information about two large that best examples potential human supergenes. In addition, do an integrative analysis newest data to understand better their functional effects underlying genetic changes. We have found highly divergent haplotypes 17q21.31 inversion approximately 1.5 Mb phenotypic associations, with consistent brain-related traits, red white blood cells, lung function, male female characteristics disease risk. By combining gene expression nucleotide variation data, also analysed molecular differences between haplotypes, including duplications, amino acid substitutions regulatory changes, identify CRHR1, KANLS1 MAPT as good candidates be responsible for these phenotypes. The situation is more complex 8p23.1 inversion, where there no clear differentiation. However, associated several related phenotypes could linked specific one orientation. Our work, therefore, contributes characterization both exceptional variants illustrates important role inversions. This article part theme issue 'Genomic architecture supergenes: causes evolutionary consequences'.

Language: Английский

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Genomic hotspots of chromosome rearrangements explain conserved synteny despite high rates of chromosome evolution in a holocentric lineage

Molecular Ecology, Journal Year: 2023, Volume and Issue: 33(24)

Published: July 24, 2023

Holocentric organisms, unlike typical monocentric have kinetochore activity distributed along almost the whole length of chromosome. Because this, chromosome rearrangements through fission and fusion are more likely to become fixed in holocentric species, which may account for extraordinary rates evolution that many lineages exhibit. Long blocks genome synteny been reported animals with chromosomes despite high rearrangements. Nothing is known from plants, however, fact holocentricity appears played a key role diversification one largest angiosperm genera, Carex (Cyperaceae). In current study, we compared genomes species distantly related Cyperaceae characterize conserved rearranged regions. Our analyses span divergence times ranging between 2 50 million years. We also C. scoparia chromosome-level assembly linkage map same study at population level suppression recombination patterns. found longer than expected under null model random rearrangement breakpoints, even very species. repetitive DNA be non-randomly associated holocentromeres regions genome. The evidence sedges suggests genomic hotspots shape recombination, gene order crossability sedges. This finding help explain why able maintain cohesion face interspecific

Language: Английский

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Unraveling the complex role of MAPT-containing H1 and H2 haplotypes in neurodegenerative diseases

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: May 29, 2024

Abstract A ~ 1 Mb inversion polymorphism exists within the 17q21.31 locus of human genome as direct (H1) and inverted (H2) haplotype clades. This region demonstrates high linkage disequilibrium, but frequency each differs across ancestries. While H1 in all populations shows a normal pattern genetic variability recombination, H2 is enriched European ancestry populations, less frequent African nearly absent East Asian populations. known risk factor for several neurodegenerative diseases, has been associated with many other traits, suggesting its importance cellular phenotypes brain entire body. Conversely, protective these predisposition to recurrent microdeletion syndromes neurodevelopmental disorders such autism. Many single nucleotide variants copy number define H1/H2 haplotypes sub-haplotypes, identifying causal variant(s) specific diseases complex due extended equilibrium. In this review, we assess current knowledge regarding genomic structure, gene expression, phenotypes, disease association. We discuss recent discoveries challenges, evaluate gaps knowledge, highlight understanding effect promote advances precision medicine drug discovery diseases. Graphical

Language: Английский

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MAPT haplotype-associated transcriptomic changes in progressive supranuclear palsy

Acta Neuropathologica Communications, Journal Year: 2024, Volume and Issue: 12(1)

Published: Aug. 17, 2024

Progressive supranuclear palsy (PSP) is a neurodegenerative movement and cognitive disorder characterized by abnormal accumulation of the microtubule-associated protein tau in brain. Biochemically, inclusions PSP are enriched for proteoforms with four microtubule-binding domain repeats (4R), an isoform that arises from alternative pre-mRNA splicing. While preferential aggregation reduced degradation 4R thought to play role inclusion formation toxicity, hypothesis altered expression mRNA isoforms plays causal role. This stems observation associated common variation gene (MAPT) at 17q21.31 locus which contains low copy number flanking large recurrent genomic inversion. The complex structural changes give rise two dominant haplotypes, termed H1 H2, have potential markedly influence expression. Here, we explored haplotype-dependent differences using bulk RNA-seq dataset derived human post-mortem brain tissue (n = 84) controls 77) rigorous computational pipeline, including We found 3579 differentially expressed genes temporal cortex 10,011 cerebellum. also 7214 differential splicing events 18,802 In cerebellum, total levels proportion transcripts encoding were significantly increased compared controls. cortex, reads was cases haplotype cortex. Further, observed marked difference KANSL1 strongly both regions. These findings support sporadic increases might this disorder.

Language: Английский

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