Biology subjects

Huang, Q. Q.

Publications and source records attributed to Huang, Q. Q..

7 recordsLinked to original sources

bioRxiv2024

The impact of ancestral, environmental and genetic influences on germline de novo mutation rates and spectra

De novo germline mutation is an important factor in the evolution of allelic diversity and disease predisposition in a population. Here, we study the influence of genetically-inferred ancestry and environmental factors on de novo mutation rates and spectra. Using a genetically diverse sample of [~]10K whole-genome sequenced trios, one of the largest de novo mutation catalogues to date, we found that genetically-inferred ancestry is associated with modest but significant changes in both germline mutation rate and spectra across continental populations. These effects may be due to genetic or environmental factors correlated with ancestry. We find epidemiological evidence that exposure to tobacco smoke is significantly associated with increased de novo mutation rate, but it does not mediate the observed ancestry effects. Investigation of several other potential mutagenic factors using Mendelian randomisation showed no consistent effects, except for age of menopause, where increased age corresponded to a reduction in de novo mutation rate. Overall, our study presents evidence on new factors influencing de novo mutational rate and spectra.

genetics↗

bioRxiv2022

The genetics of cortical organisation and development: a study of 2,347 neuroimaging phenotypes

Our understanding of the genetic architecture of the human cerebral cortex is limited both in terms of the diversity of brain structural phenotypes and the anatomical granularity of their associations with genetic variants. Here, we conducted genome-wide association meta-analysis of 13 structural and diffusion magnetic resonance imaging derived cortical phenotypes, measured globally and at 180 bilaterally averaged regions in 36,843 individuals from the UK Biobank and the ABCD cohorts. These phenotypes include cortical thickness, surface area, grey matter volume, and measures of folding, neurite density, and water diffusion. We identified 4,349 experiment-wide significant loci associated with global and regional phenotypes. Multiple lines of analyses identified four genetic latent structures and causal relationships between surface area and some measures of cortical folding. These latent structures partly relate to different underlying gene expression trajectories during development and are enriched for different cell types. We also identified differential enrichment for neurodevelopmental and constrained genes and demonstrate that common genetic variants associated with surface area and volume specifically are associated with cephalic disorders. Finally, we identified complex inter-phenotype and inter-regional genetic relationships among the 13 phenotypes which reflect developmental differences among them. These analyses help refine the role of common genetic variants in human cortical development and organisation. One sentence summaryGWAS of 2,347 neuroimaging phenotypes shed light on the global and regional genetic organisation of the cortex, underlying cellular and developmental processes, and links to neurodevelopmental and cephalic disorders.

neuroscience↗

bioRxiv2022

Multi-ancestry GWAS of major depression aids locus discovery, fine-mapping, gene prioritisation, and causal inference

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 studies with 88,316 MD cases and 902,757 controls to previously reported data from individuals of European ancestry. This includes samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latinx participants (32%). The multi-ancestry GWAS identified 190 significantly associated loci, 53 of them novel. For previously reported loci from GWAS in European ancestry the power-adjusted transferability ratio was 0.6 in the Hispanic/Latinx group and 0.3 in each of the other groups. Fine-mapping benefited from additional sample diversity: the number of credible sets with [≤]5 variants increased from 3 to 12. A transcriptome-wide association study identified 354 significantly associated genes, 205 of them novel. Mendelian Randomisation showed a bidirectional relationship with BMI exclusively in samples of European ancestry. This first multi-ancestry GWAS of MD demonstrates the importance of large diverse samples for the identification of target genes and putative mechanisms.

genetics↗

bioRxiv2020

Fine-scale population structure and demographic history of British Pakistanis

Previous genetic and public health research in the Pakistani population has focused on the role of consanguinity in increasing recessive disease risk, but little is known about its recent population history or the effects of endogamy. Here, we investigate fine-scale population structure, history and consanguinity patterns using genetic and questionnaire data from >4,000 British Pakistani individuals, mostly with roots in Azad Kashmir and Punjab. We reveal strong recent population structure driven by the biraderi social stratification system. We find that all subgroups have had low effective population sizes (Ne) over the last 50 generations, with some showing a decrease in Ne 15-20 generations ago that has resulted in extensive identity-by-descent sharing and increased homozygosity. Using new theory, we show that the footprint of regions of homozygosity in the two largest subgroups is about twice that expected naively based on the self-reported consanguinity rates and the inferred historical Ne trajectory. These results demonstrate the impact of the cultural practices of endogamy and consanguinity on population structure and genomic diversity in British Pakistanis, and have important implications for medical genetic studies.

genomics↗

bioRxiv2019

Neonatal genetics of gene expression reveal the origins of autoimmune and allergic disease risk

Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we collected cord blood samples from a birth cohort and mapped expression quantitative trait loci (eQTLs) in resting monocytes and CD4+ T cells as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis-eQTLs were largely specific to cell type or stimulation, and response eQTLs were identified for 31% of genes with cis-eQTLs (eGenes) in monocytes and 52% of eGenes in CD4+ T cells. We identified trans-eQTLs and mapped cis regulatory factors which act as mediators of trans effects. There was extensive colocalisation of causal variants for cell type- and stimulation-specific neonatal cis-eQTLs and those of autoimmune and allergic diseases, in particular CTSH (Cathepsin H) which showed widespread colocalisation across diseases. Mendelian randomisation showed causal neonatal gene transcription effects on disease risk for BTN3A2, HLA-C and many other genes. Our study elucidates the genetics of gene expression in neonatal conditions and cell types as well as the aetiological origins of autoimmune and allergic diseases.

genetics↗

bioRxiv2019

Multivariate genome-wide association analysis of a cytokine network reveals variants with widespread immune, haematological and cardiometabolic pleiotropy

Cytokines are essential regulatory components of the immune system and their aberrant levels have been linked to many disease states. Despite increasing evidence that cytokines operate in concert, many of the physiological interactions between cytokines, and the shared genetic architecture that underlie them, remain unknown. Here we aimed to identify and characterise genetic variants with pleiotropic effects on cytokines - to do this we performed a multivariate genome-wide association study on a correlation network of 11 circulating cytokines measured in 9,263 individuals. Meta-analysis identified a total of 8 loci significantly associated with the cytokine network, of which two (PDGFRB and ABO) had not been detected previously. Bayesian colocalisation analysis revealed shared causal variants between the eight cytokine loci and other traits; in particular, cytokine network variants at the ABO, SERPINE2, and ZFPM2 loci showed pleiotropic effects on the production of immune-related proteins; on metabolic traits such as lipoprotein and lipid levels; on blood-cell related traits such as platelet count; and on disease traits such as coronary artery disease and type 2 diabetes.

genomics↗

bioRxiv2017

Power, false discovery rate and Winner’s Curse in eQTL studies

Investigation of the genetic architecture of gene expression traits has aided interpretation of disease and trait-associated genetic variants, however key aspects of expression quantitative trait (eQTL) study design and analysis remain understudied. We used extensive, empirically-driven simulations to explore eQTL study design and the performance of various analysis strategies. Across multiple testing correction methods, false discoveries of genes with eQTLs (eGenes) were substantially inflated when false discovery rate (FDR) control was applied to all tests, and only appropriately controlled using hierarchical procedures. All multiple testing correction procedures had low power and inflated FDR for eGenes whose causal SNPs had small allele frequencies using small sample sizes (e.g. frequency <10% in 100 samples), indicating that even moderately low frequency eQTL SNPs (eSNPs) in these studies are enriched for false discoveries. In scenarios with [≥]80% power, the top eSNP was the true simulated eSNP 90% of the time, but substantially less frequently for very common eSNPs (minor allele frequencies >25%). Overestimation of eQTL effect sizes, so-called \"Winners Curse\", was common in low and moderate power settings. To address this, we developed a bootstrap method (BootstrapQTL) which led to more accurate effect size estimation. These insights provide a foundation for future eQTL studies, especially those with sampling constraints and subtly different conditions.

genetics↗