Genetic influences on susceptibility to rheumatoid arthritis in African-Americans

Laufer, Vincent A.; Tiwari, Hemant K.; Reynolds, Richard J.; Danila, Maria I.; Wang, Jelai; Edberg, Jeffrey C.; Kimberly, Robert P.; Kottyan, Leah C.; Harley, John B.; Mikuls, Ted R.; Gregersen, Peter K.; Absher, Devin; Langefeld, Carl D.; Arnett, Donna K.; Bridges, S. Louis

doi:10.1093/hmg/ddy395

Cited by 64 publications

(45 citation statements)

References 98 publications

(109 reference statements)

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“…Also, various exonic VNTR maps within a very short distance of genome-wide significant loci associated with different GWAS studies. Examples are height ( ACAN locus 37 ), hair morphology ( TCHH locus 87 ), Asthma/Atopy ( FLG locus 88 , 89 ), Rheumatoid arthritis ( ICOSLG locus 90 ), and diastolic blood pressure ( HRCT1 locus 91 ). Future studies will have to indicate whether these VNTRs indeed explain at least part of the disease associations as identified in the respective GWAS studies.…”

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confidence: 99%

Extreme enrichment of VNTR-associated polymorphicity in human subtelomeres: genes with most VNTRs are predominantly expressed in the brain

et al. 2020

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The human genome harbors numerous structural variants (SVs) which, due to their repetitive nature, are currently underexplored in short-read whole-genome sequencing approaches. Using single-molecule, real-time (SMRT) long-read sequencing technology in combination with FALCON-Unzip, we generated a de novo assembly of the diploid genome of a 115-year-old Dutch cognitively healthy woman. We combined this assembly with two previously published haploid assemblies (CHM1 and CHM13) and the GRCh38 reference genome to create a compendium of SVs that occur across five independent human haplotypes using the graph-based multi-genome aligner REVEAL. Across these five haplotypes, we detected 31,680 euchromatic SVs (>50 bp). Of these, ~62% were comprised of repetitive sequences with ‘variable number tandem repeats’ (VNTRs), ~10% were mobile elements (Alu, L1, and SVA), while the remaining variants were inversions and indels. We observed that VNTRs with GC-content >60% and repeat patterns longer than 15 bp were 21-fold enriched in the subtelomeric regions (within 5 Mb of the ends of chromosome arms). VNTR lengths can expand to exceed a critical length which is associated with impaired gene transcription. The genes that contained most VNTRs, of which PTPRN2 and DLGAP2 are the most prominent examples, were found to be predominantly expressed in the brain and associated with a wide variety of neurological disorders. Repeat-induced variation represents a sizeable fraction of the genetic variation in human genomes and should be included in investigations of genetic factors associated with phenotypic traits, specifically those associated with neurological disorders. We make available the long and short-read sequence data of the supercentenarian genome, and a compendium of SVs as identified across 5 human haplotypes.

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confidence: 99%

Extreme enrichment of VNTR-associated polymorphicity in human subtelomeres: genes with most VNTRs are predominantly expressed in the brain

et al. 2020

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“…A. Ferreira et al, 2017;Kichaev et al, 2019;Laufer et al, 2019;Lessard et al, 2013). The second is HYOU1, which has been associated with BMI and Post-FEV1/FVC (Lutz et al, 2015;Pulit et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Integrative genomic analysis in African American children with asthma finds 3 novel loci associated with lung function

Goddard

Keys

Mak

et al. 2020

Preprint

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27Bronchodilator drugs are commonly prescribed for treatment and management of obstructive lung function 28 present with diseases such as asthma. Administration of bronchodilator medication can partially or fully restore 29 lung function as measured by pulmonary function tests. The genetics of baseline lung function measures taken 30 prior to bronchodilator medication has been extensively studied, and the genetics of the bronchodilator 31 response itself has received some attention. However, few studies have focused on the genetics of post-32 bronchodilator lung function. To address this gap, we analyzed lung function phenotypes in 1,103 subjects from 33 the Study of African Americans, Asthma, Genes, and Environment (SAGE), a pediatric asthma case-control 34 cohort, using an integrative genomic analysis approach that combined genotype, locus-specific genetic 35 ancestry, and functional annotation information. We integrated genome-wide association study (GWAS) results 36 with an admixture mapping scan of three pulmonary function tests (FEV1, FVC, and FEV1/FVC) taken before and 37 after albuterol bronchodilator administration on the same subjects, yielding six traits. We identified 18 GWAS 38 loci, and 5 additional loci from admixture mapping, spanning several known and novel lung function candidate 39 genes. Most loci identified via admixture mapping exhibited wide variation in minor allele frequency across 40 genotyped global populations. Functional fine-mapping revealed an enrichment of epigenetic annotations from 41 peripheral blood mononuclear cells, fetal lung tissue, and lung fibroblasts. Our results point to three novel 42 potential genetic drivers of pre-and post-bronchodilator lung function: ADAMTS1, RAD54B, and EGLN3. 43 Keywords 44 African-American, admixture, GWAS, lung function, asthma, integrative genomic analysis 45 130 total of six phenotypes were assessed for genotype association: pre-BD FEV1 (Pre-FEV1), pre-BD FVC (Pre-FVC), 131 pre-BD FEV1/FVC (Pre-FEV1/FVC), post-BD FEV1 (Post-FEV1), post-BD FVC (Post-FVC), and post-BD FEV1/FVC 132 (Post-FEV1/FVC). All phenotype values were normalized based on the expected lung function values calculated 133 from the Hankinson equations (Hankinson et al., 1999), which account for age, sex, height, and self-reported 134 ethnicity. Phenotype distributions were checked for normality and to detect outliers. Outliers were determined 135 using the method of Tukey fences (John Tukey, 1977). For each phenotype, we computed the first quartile value 136 (Q1), the third quartile value (Q3), and the interquartile range (IQR). We declared as outliers all values outside 137 of the range 138 ["1 − 3('"(), "3 + 3('"()].

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“…The Consortium for the Longitudinal Evaluation of African‐Americans with Early Rheumatoid Arthritis (CLEAR) study was an observational case‐control study beginning in 2000 to investigate genetic influences on RA (Bridges et al, 2002; Laufer et al, 2019). Local IRB approval was obtained to use existing genotyping data from the Illumina Omni1S array on a subset of participants (625 RA cases and 879 controls) in this MR analysis.…”

Section: Real Data Analysismentioning

confidence: 99%

A novel Mendelian randomization method with binary risk factor and outcome

Allman

Aban

Long

et al. 2021

Genetic Epidemiology

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Background Mendelian randomization (MR) applies instrumental variable (IV) methods to observational data using a genetic variant as an IV. Several Monte‐Carlo studies investigate the performance of MR methods with binary outcomes, but few consider them in conjunction with binary risk factors. Objective To develop a novel MR estimator for scenarios with a binary risk factor and outcome; and compare to existing MR estimators via simulations and real data analysis. Methods A bivariate Bernoulli distribution is adapted to the IV setting. Empirical bias and asymptotic coverage probabilities are estimated via simulations. The proposed method is compared to the Wald method, two‐stage predictor substitution (2SPS), two‐stage residual inclusion (2SRI), and the generalized method of moments (GMM). An analysis is performed using existing data from the CLEAR study to estimate the potential causal effect of smoking on rheumatoid arthritis risk in African Americans. Results Bias was low for the proposed method and comparable to 2SPS. The Wald method was often biased towards the null. Coverage was adequate for the proposed method, 2SPS, and 2SRI. Coverage for the Wald and GMM methods was poor in several scenarios. The causal effect of ever smoking on rheumatoid arthritis risk was not statistically significant using a variety of genetic instruments. Conclusions Simulations suggest the proposed MR method is sound with binary risk factors and outcomes, and comparable to 2SPS and 2SRI in terms of bias. The proposed method also provides more natural framework for hypothesis testing compared to 2SPS or 2SRI, which require ad‐hoc variance adjustments.

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Genetic influences on susceptibility to rheumatoid arthritis in African-Americans

Cited by 64 publications

References 98 publications

Extreme enrichment of VNTR-associated polymorphicity in human subtelomeres: genes with most VNTRs are predominantly expressed in the brain

Extreme enrichment of VNTR-associated polymorphicity in human subtelomeres: genes with most VNTRs are predominantly expressed in the brain

Integrative genomic analysis in African American children with asthma finds 3 novel loci associated with lung function

A novel Mendelian randomization method with binary risk factor and outcome

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