Publications by authors named "Jonathan P Bradfield"

Genetic effects on changes in human traits over time are understudied and may have important pathophysiological impact. We propose a framework that enables data quality control, implements mixed models to evaluate trajectories of change in traits, and estimates phenotypes to identify age-varying genetic effects in GWAS. Using childhood BMI as an example trait, we included 71,336 participants from six cohorts and estimated the slope and area under the BMI curve within four time periods (infancy, early childhood, late childhood and adolescence) for each participant, in addition to the age and BMI at the adiposity peak and the adiposity rebound.

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  • A large study with nearly 30,000 parent-offspring pairs from Norway identified a key genetic variant in UGT1A4 that reduces jaundice risk significantly.
  • The research shows different genetic factors influence neonatal jaundice compared to adult bilirubin levels, indicating unique genetic mechanisms at play.
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  • Scientists looked at the timing of when girls start their periods (called menarche) and how it can affect their health later in life.
  • They studied about 800,000 women and found over a thousand genetic signals that influence when menstruation starts.
  • Some women have a much higher chance of starting their periods too early or too late based on their genetic makeup, suggesting that genes play a big role in this process!
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The ch12q13 locus is among the most significant childhood obesity loci identified in genome-wide association studies. This locus resides in a non-coding region within FAIM2; thus, the underlying causal variant(s) presumably influence disease susceptibility via cis-regulation. We implicated rs7132908 as a putative causal variant by leveraging our in-house 3D genomic data and public domain datasets.

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Genetic effects on changes in human traits over time are understudied and may have important pathophysiological impact. We propose a framework that enables data quality control, implements mixed models to evaluate trajectories of change in traits, and estimates phenotypes to identify age-varying genetic effects in genome-wide association studies (GWASs). Using childhood body mass index (BMI) as an example, we included 71,336 participants from six cohorts and estimated the slope and area under the BMI curve within four time periods (infancy, early childhood, late childhood and adolescence) for each participant, in addition to the age and BMI at the adiposity peak and the adiposity rebound.

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Regions under balancing selection are characterized by dense polymorphisms and multiple persistent haplotypes, along with other sequence complexities. Successful identification of these patterns depends on both the statistical approach and the quality of sequencing. To address this challenge, at first, a new statistical method called LD-ABF was developed, employing efficient Bayesian techniques to effectively test for balancing selection.

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  • - This study explores how growth patterns during puberty relate to future health outcomes by analyzing height data from about 56,000 individuals across various ancestries using a technique called SITAR.
  • - The researchers identified 26 significant genetic loci linked to height growth during puberty and found that different growth rates are associated with various health risks, like type 2 diabetes and heart conditions.
  • - The findings suggest that there are multiple growth trajectories during puberty, each influencing adult health differently, indicating that no single growth pattern is the "best" for lifelong health outcomes.
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  • - The study investigates the genetic factors influencing the timing of parturition, finding 22 genetic loci associated with gestational duration from a large sample of almost 200,000 participants.
  • - A meta-analysis of preterm delivery cases identified six genetic loci and highlighted similarities between genetic influences on gestational duration and preterm birth.
  • - The research reveals that maternal genetics play a significant role in gestational timing, with some variants negatively impacting fetal birth weight, indicating a complex interaction between maternal and fetal genetics.
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  • Type 1 diabetes is linked to autoimmune destruction of insulin-producing cells, making early onset more challenging to manage; researchers conducted a genome-wide association study (GWAS) to explore genetic factors related to the age of diagnosis.
  • The study involved analyzing data from over 4,500 cases and identified genetic associations, particularly a significant link with the HLA-DQB1 gene and a related variant in the NELL1 gene that could lead to an earlier onset of diabetes.
  • Findings suggest that the gene HTATIP2 influences T cell behavior and may contribute to type 1 diabetes, indicating a potential new genetic target for further research; ongoing studies with larger groups could uncover more genetic factors.
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  • Common SNPs may account for 40-50% of human height variation, and this study identifies 12,111 SNPs linked to height from a large sample of 5.4 million individuals.
  • These SNPs cluster in 7,209 genomic segments, encompassing about 21% of the genome and showing varying densities enriched in relevant genes.
  • While these SNPs explain a substantial portion of height variance in European populations (40-45%), their predictive power is lower (10-24%) in other ancestries, suggesting a need for more research to enhance understanding in diverse populations.
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  • Researchers studied the genetic connections to blood fats using data from 1.6 million people from different backgrounds to understand why certain fats are higher or lower in the body.
  • They looked at special genes and how they interact in the liver and fat cells, finding that the liver plays a big part in controlling fat levels.
  • Two specific genes, CREBRF and RRBP1, were highlighted as important in understanding how our bodies manage fats due to strong supporting evidence.
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Background: Head circumference is associated with intelligence and tracks from childhood into adulthood.

Methods: We performed a genome-wide association study meta-analysis and follow-up of head circumference in a total of 29,192 participants between 6 and 30 months of age.

Results: Seven loci reached genome-wide significance in the combined discovery and replication analysis of which three loci near ARFGEF2, MYCL1, and TOP1, were novel.

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Objective: Juvenile idiopathic arthritis (JIA) is the most common chronic immune-mediated joint disease among children and encompasses a heterogeneous group of immune-mediated joint disorders classified into 7 subtypes according to clinical presentation. However, phenotype overlap and biologic evidence suggest a shared mechanistic basis between subtypes. This study was undertaken to systematically investigate shared genetic underpinnings of JIA subtypes.

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Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels, heart disease remains the leading cause of death worldwide. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease.

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The hypothalamus regulates metabolic homeostasis by influencing behavior and endocrine systems. Given its role governing key traits, such as body weight and reproductive timing, understanding the genetic regulation of hypothalamic development and function could yield insights into disease pathogenesis. However, given its inaccessibility, studying human hypothalamic gene regulation has proven challenging.

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We performed a genome-wide association study (GWAS) to identify genetic variation associated with common forms of idiopathic generalized epilepsy (GE) and focal epilepsy (FE). Using a cohort of 2220 patients and 14,448 controls, we searched for single nucleotide polymorphisms (SNPs) associated with GE, FE and both forms combined. We did not find any SNPs that reached genome-wide statistical significance ( ≤ 5 × 10) when comparing all cases to all controls, and few SNPs of interest comparing FE cases to controls.

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With polygenic risk score (PRS) for autoimmune type 1 diabetes (T1D), this study identified T1D cases with low T1D PRS and searched for susceptibility loci in these cases. Our hypothesis is that genetic effects (likely mediated by relatively rare genetic variants) of non-mainstream (or non-autoimmune) T1D might have been diluted in the previous studies on T1D cases in general. Two cohorts for the PRS modeling and testing respectively were included.

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Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC).

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Type 1 diabetes (T1D) is a heterogeneous disease. This study identified T1D cases with low polygenic risk score (PRS) to better represent T1D cases with less prominent autoimmune response (T1bD), and performed a gene-based association study to identify novel susceptibility loci in two independent cohorts, characterized by low PRS. The Notch ligand Delta-like 1 gene (DLL1) was identified with genome-wide significance in both cohorts, highlighting the roles of DLL1 genetic variants in T1D patients with low PRS, supported by functional evidence from a recent study by Rubey et al.

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The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses.

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Background And Aims: Among the >240 genetic loci described to date which confer susceptibility to inflammatory bowel disease, a small subset have been fine-mapped to an individual, non-coding single nucleotide polymorphism [SNP]. To illustrate a model mechanism by which a presumed-causal non-coding SNP can function, we analysed rs1887428, located in the promoter region of the Janus kinase 2 [JAK2] gene.

Methods: We utilized comparative affinity purification-mass spectrometry, DNA-protein binding assays, CRISPR/Cas9 genome editing, transcriptome sequencing and methylome quantitative trait locus methods to characterize the role of this SNP.

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