Rapid decline in estimated glomerular filtration rate in sickle cell anemia: Results of a multicenter pooled analysis

Chronic kidney disease (CKD), typically defined as kidney damage or decreased kidney function for 3 or more months, is common in sickle cell disease (SCD). Increasing evidence suggests that the glomerulopathy of SCD is progressive. CKD is associated with increased mortality in SCD. Based on single center studies, we previously reported on the high prevalence of rapid decline in kidney function, defined as estimated glomerular filtration rate (eGFR) loss >3.0 mL/min/1.73 m2per year, in SCD. In the present study, we further examine rapid eGFR decline in sickle cell anemia, using a pooled analysis of patients to better characterize factors associated with such decline and its association with mortality

Longitudinal study of glomerular hyperfiltration in adults with sickle cell anemia: a multicenter pooled analysis

Glomerular hyperfiltration is common in young sickle cell anemia patients and precedes development of overt kidney disease. In this multicenter pooled cohort, we characterized hyperfiltration and its decline to normal range in adult patients. Glomerular filtration rate (GFR) was estimated using the creatinine-based 2009 CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation omitting race adjustment and the 2021 CKD-EPI equation. Using CKD-EPI–2009, 506 patients had baseline estimated GFR (eGFR) $90 mL/min per 1.73 m2, median age of 24 (interquartile range [IQR], 19-34) years and 5.17 years of follow-up. The prevalence of hyperfiltration (eGFR$140 and $130 mL/min per 1.73 m2 for men and women, respectively) was 38.3%. Using CKD-EPI–2009, baseline hyperfiltration was less likely with older age (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.73-0.83; P, .0001), male sex (OR, 0.32; 95% CI, 0.18-0.58; P 5 .0002), and higher weight (OR, 0.96; 95% CI, 0.94-0.99; P 5 .001). Using CKD-EPI–2021, hyperfiltration was similarly less likely with older age (OR, 0.75; 95% CI, 0.70-0.81; P, .0001), male sex (OR, 0.24; 95% CI, 0.13-0.44; P, .0001), and higher weight (OR, 0.97; 95% CI, 0.95-0.99; P 5 .004). In patients with baseline hyperfiltration, eGFR declined to normal values at a median age of 26.2 years. Using CKD-EPI–2009, this decline was associated with male sex (HR, 2.20; 95% CI, 1.26-3.87; P 5 .006), systolic blood pressure (hazard ratio [HR], 1.02; 95% CI, 1.01-1.04; P 5 .01), and hydroxyurea use (HR, 1.74; 95% CI, 1.002-3.03; P 5 .05). Using CKD-EPI–2021, decline of eGFR to normal was only associated with male sex (HR, 3.39; 95% CI, 2.01-5.69; P, .0001). Decline to normal eGFR range from hyperfiltration occurs earlier in males, those on hydroxyurea, and with higher systolic blood pressure

Rare genetic variants explain missing heritability in smoking

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this ‘missing heritability’. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability (hSNP2) was estimated from 0.13 to 0.28 (s.e., 0.10–0.13) in European ancestries, with 35–74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5–4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability (hped2, 0.18–0.34). In the African ancestry samples, hSNP2 was estimated from 0.03 to 0.33 (s.e., 0.09–0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking

Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes

Lexical availability and grammatical encoding scope during spoken sentence production

Three sentence production experiments investigate the relationship between lexical and structural processing scope. Speakers generated sentences with varying phrase structures in response to visual displays (e.g., The dog and the hat move above the fork and the tree/The dog moves above the hat and the fork and the tree). On half of the trials, one of the pictures in the arrays was previewed. Filler sentences varied preview position and sentence structure from trial to trial. When speakers could not anticipate the position of the previewed picture in the upcoming sentence (Experiment 1), preview benefit for pictures corresponding to the second noun to be produced was limited to pictures that fell within the sentence-initial phrase. When the linear position of the previewed picture was predictable, preview benefits were observed for the second noun to be produced, irrespective of phrase position (Experiment 2). However, no preview benefits were observed for the third noun to be produced (Experiment 3). In contrast, significant effects of initial phrase structure were observed in all experiments, with latencies increasing with initial phrase length. The results are consistent with speakers operating a phrasal scope for structural planning within which the scope of lexical access can vary