Despite the dramatic underrepresentation of non-European populations in human genetics studies, researchers continue to exclude participants of non-European ancestry, as well as variants rare in ...European populations, even when these data are available. This practice perpetuates existing research disparities and can lead to important and large effect size associations being missed. Here, we conducted genome-wide association studies (GWAS) of 31 serum and urine biomarker quantitative traits in African (n = 9354), East Asian (n = 2559), and South Asian (n = 9823) ancestry UK Biobank (UKBB) participants. We adjusted for all known GWAS catalog variants for each trait, as well as novel signals identified in a recent European ancestry-focused analysis of UKBB participants. We identify 7 novel signals in African ancestry and 2 novel signals in South Asian ancestry participants (p < 1.61E-10). Many of these signals are highly plausible, including a cis pQTL for the gene encoding gamma-glutamyl transferase and PIEZO1 and G6PD variants with impacts on HbA1c through likely erythrocytic mechanisms. This work illustrates the importance of using the genetic data we already have in diverse populations, with novel discoveries possible in even modest sample sizes.
Methylation levels may be associated with and serve as markers to predict risk of progression of precancerous cervical lesions. We conducted an epigenome-wide association study (EWAS) of CpG ...methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2 +) following an abnormal screening test.
A prospective US cohort of 289 colposcopy patients with normal or CIN1 enrollment histology was assessed. Baseline cervical sample DNA was analyzed using Illumina HumanMethylation 450K (n = 76) or EPIC 850K (n = 213) arrays. Participants returned at provider-recommended intervals and were followed up to 5 years via medical records. We assessed continuous CpG M values for 9 cervical cancer-associated genes and time-to-progression to CIN2+. We estimated CpG-specific time-to-event ratios (TTER) and hazard ratios using adjusted, interval-censored Weibull accelerated failure time models. We also conducted an exploratory EWAS to identify novel CpGs with false discovery rate (FDR) < 0.05.
At enrollment, median age was 29.2 years; 64.0% were high-risk HPV-positive, and 54.3% were non-white. During follow-up (median 24.4 months), 15 participants progressed to CIN2+. Greater methylation levels were associated with a shorter time-to-CIN2+ for CADM1 cg03505501 (TTER = 0.28; 95%CI 0.12, 0.63; FDR = 0.03) and RARB Cluster 1 (TTER = 0.46; 95% CI 0.29, 0.71; FDR = 0.01). There was evidence of similar trends for DAPK1 cg14286732, PAX1 cg07213060, and PAX1 Cluster 1. The EWAS detected 336 novel progression-associated CpGs, including those located in CpG islands associated with genes FGF22, TOX, COL18A1, GPM6A, XAB2, TIMP2, GSPT1, NR4A2, and APBB1IP.
Using prospective time-to-event data, we detected associations between CADM1-, DAPK1-, PAX1-, and RARB-related CpGs and cervical disease progression, and we identified novel progression-associated CpGs.
Methylation levels at novel CpG sites may help identify individuals with ≤CIN1 histology at higher risk of progression to CIN2+ and inform risk-based cervical cancer screening guidelines.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
: Faster rates of cognitive decline are likely to result in earlier onset of cognitive impairment and dementia. d-galactose, a derivative of lactose, is used in animal studies to induce ...neurodegeneration. Milk is the primary source of lactose in the human diet, and its effects on cognitive decline have not been fully evaluated.
: Assess the association of milk intake with change in cognitive function over 20 years.
: A total of 13,751 participants of the Atherosclerosis Risk in Communities (ARIC) cohort completed a food frequency questionnaire and three neurocognitive evaluations from 1990 through 2013. Two single nucleotide polymorphisms (SNPs) were used to determine lactase persistence (LCT-13910 C/T for Whites and LCT-14010 G/C for Blacks). Mixed-effects models were used to study the association of milk intake with cognitive change. Multiple imputations by chained equations were used to account for attrition.
: Milk intake greater than 1 glass/day was associated with greater decline in the global z-score over a 20-year period. The difference in decline was 0.10 (95% CI: 0.16, 0.03) z-scores, or an additional 10% decline, relative to the group reporting "almost never" consuming milk.
: Replication of these results is warranted in diverse populations with greater milk intake and higher variability of lactase persistence genotype.
Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear ...whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10−5. Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r2 > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10−8) and DHX34 (rs4802349, p = 1.2 × 10−7), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.
Achieving confidence in the causality of a disease locus is a complex task that often requires supporting data from both statistical genetics and clinical genomics. Here we describe a combined ...approach to identify and characterize a genetic disorder that leverages distantly related patients in a health system and population-scale mapping. We utilize genomic data to uncover components of distant pedigrees, in the absence of recorded pedigree information, in the multi-ethnic Bio
biobank in New York City. By linking to medical records, we discover a locus associated with both elevated genetic relatedness and extreme short stature. We link the gene,
, with a little-known genetic disease, previously thought to be rare and recessive. We demonstrate that disease manifests in both heterozygotes and homozygotes, indicating a common collagen disorder impacting up to 2% of individuals of Puerto Rican ancestry, leading to a better understanding of the continuum of complex and Mendelian disease.
Background Research examining the role of obesity in cardiovascular disease (CVD) often fails to adequately consider heterogeneity in obesity severity, distribution, and duration. Methods and Results ...We here use multivariate latent class mixed models in the biracial Atherosclerosis Risk in Communities study (N=14 514; mean age=54 years; 55% female) to associate obesity subclasses (derived from body mass index, waist circumference, self-reported weight at age 25, tricep skinfold, and calf circumference across up to four triennial visits) with total mortality, incident CVD, and CVD risk factors. We identified four obesity subclasses, summarized by their body mass index and waist circumference slope as decline (4.1%), stable/slow decline (67.8%), moderate increase (24.6%), and rapid increase (3.6%) subclasses. Compared with participants in the stable/slow decline subclass, the decline subclass was associated with elevated mortality (hazard ratio HR 1.45, 95% CI 1.31, 1.60,
<0.0001) and with heart failure (HR 1.41, 95% CI 1.22, 1.63,
<0.0001), stroke (HR 1.53, 95% CI 1.22, 1.92,
=0.0002), and coronary heart disease (HR 1.36, 95% CI 1.14, 1.63,
=0.0008), adjusting for baseline body mass index and CVD risk factor profile. The moderate increase latent class was not associated with any significant differences in CVD risk as compared to the stable/slow decline latent class and was associated with a lower overall risk of mortality (HR 0.85, 95% CI 0.80, 0.90,
<0.0001), despite higher body mass index at baseline. The rapid increase latent class was associated with a higher risk of heart failure versus the stable/slow decline latent class (HR 1.34, 95% CI 1.10, 1.62,
=0.004). Conclusions Consideration of heterogeneity and longitudinal changes in obesity measures is needed in clinical care for a more precision-oriented view of CVD risk.
ObjectivesInfant anthropometric growth varies across socioeconomic factors, including maternal education and income, and may serve as an indicator of environmental influences in early life with ...long-term health consequences. Previous research has identified sociodemographic gradients in growth with a focus on the first year and beyond, but estimates are sparse for growth before 6 months. Thus, our objective was to examine the relationship between sociodemographic factors and infant growth patterns between birth and 5 months of age.DesignProspective cohort study.SettingsLow-income to middle-income neighbourhoods in Santiago, Chile (1991–1996).Participants1412 participants from a randomised iron-deficiency anaemia preventive trial in healthy infants.Main outcome measuresLongitudinal anthropometrics including monthly weight (kg), length (cm) and weight-for-length (WFL) values. For each measure, we estimated three individual-level growth parameters (size, timing and velocity) from SuperImposition by Translation and Rotation models. Size and timing changes represent vertical and horizontal growth curve shifts, respectively, and velocity change represents growth rate shifts. We estimated the linear association between growth parameters and gestational age, maternal age, education and socioeconomic position (SEP).ResultsLower SEP was associated with a slower linear (length) velocity growth parameter (−0.22, 95% CI –0.31 to –0.13)—outcome units are per cent change in velocity from the average growth curve. Lower SEP was associated with later WFL growth timing as demonstrated through the tempo growth parameter for females (0.25, 95% CI 0.05 to 0.42)—outcome units are shifts in days from the average growth curve. We found no evidence of associations between SEP and the weight size, timing or velocity growth rate parameters.ConclusionPrevious research on growth in older infants and children shows associations between lower SEP with slower length velocity. We found evidence supporting this association in the first 5 months of life, which may inform age-specific prevention efforts aimed at infant length growth.
Even though there has been great success in identifying lipid-associated single-nucleotide polymorphisms (SNPs), the mechanisms through which the SNPs act on each trait are poorly understood. The ...emergence of large, complex biological data sets in well-characterized cohort studies offers an opportunity to investigate the genetic effects on trait variability as a way of informing the causal genes and biochemical pathways that are involved in lipoprotein metabolism. However, methods for simultaneously analyzing multiple omics, environmental exposures, and longitudinally measured, correlated phenotypes are lacking. The purpose of our study was to demonstrate the utility of the structural equation modeling (SEM) approach to inform our understanding of the pathways by which genetic variants lead to disease risk. With the SEM method, we examine multiple pathways directly and indirectly through previously identified triglyceride (TG)-associated SNPs, methylation, and high-density lipoprotein (HDL), including sex, age, and smoking behavior, while adding in biologically plausible direct and indirect pathways. We observed significant SNP effects (
< 0.05 and directionally consistent) on TGs at visit 4 (TG4) for five loci, including rs645040 (
), rs964184 (
/
), rs4765127 (
), rs1121980 (
), and rs10401969 (
). Across these loci, we identify three with strong evidence of an indirect genetic effect on TG4 through HDL, one with evidence of pleiotropic effect on HDL and TG4, and one variant that acts on TG4 indirectly through a nearby methylation site. Such information can be used to prioritize candidate genes in regions of interest, inform mechanisms of action of methylation effects, and highlight possible genes with pleiotropic effects.
Although smoking behavior is known to affect body mass index (BMI), the potential for smoking to influence genetic associations with BMI is largely unexplored.
As part of the 'Population Architecture ...using Genomics and Epidemiology (PAGE)' Consortium, we investigated interaction between genetic risk factors associated with BMI and smoking for 10 single nucleotide polymorphisms (SNPs) previously identified in genome-wide association studies. We included 6 studies with a total of 56,466 subjects (16,750 African Americans (AA) and 39,716 European Americans (EA)). We assessed effect modification by testing an interaction term for each SNP and smoking (current vs. former/never) in the linear regression and by stratified analyses.
We did not observe strong evidence for interactions and only observed two interactions with p-values <0.1: for rs6548238/TMEM18, the risk allele (C) was associated with BMI only among AA females who were former/never smokers (β = 0.018, p = 0.002), vs. current smokers (β = 0.001, p = 0.95, p(interaction) = 0.10). For rs9939609/FTO, the A allele was more strongly associated with BMI among current smoker EA females (β = 0.017, p = 3.5 x 10(-5)), vs. former/never smokers (β = 0.006, p = 0.05, p(interaction) = 0.08).
These analyses provide limited evidence that smoking status may modify genetic effects of previously identified genetic risk factors for BMI. Larger studies are needed to follow up our results.
NCT00000611.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 ...years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10
), arthritis (GDF5 p = 4 × 10
), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
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