Robust linear regression methods in association studies

Lourenço, Vanda; Pires, Ana M.; Kirst, Matias

doi:10.1093/bioinformatics/btr006

Cited by 51 publications

(34 citation statements)

References 42 publications

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“…To account for underlying population structure, study-specific genome wide principal components generated by the program EIGENSOFT were included as covariates. (34) Given the extended pedigree structure of GRAAD-AC, a linear mixed effects model using a kinship matrix approach was employed for this cohort; (35) this method corrects for familial correlation (both known and unknown) by estimating the empirical kinship between all pairs of subjects.…”

Section: Methodsmentioning

confidence: 99%

A meta-analysis of genome-wide association studies for serum total IgE in diverse study populations

Levin

Mathias

Huang

et al. 2013

Journal of Allergy and Clinical Immunology

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Background Immunoglobulin E (IgE) is both a marker and mediator of allergic inflammation. Despite reported differences in serum total IgE levels by race-ethnicity, African American and Latino individuals have not been well represented in genetic studies of total IgE. Objective To identify the genetic predictors of serum total IgE levels. Methods We used genome wide association (GWA) data from 4,292 individuals (2,469 African Americans, 1,564 European Americans, and 259 Latinos) in the EVE Asthma Genetics Consortium. Tests for association were performed within each cohort by race-ethnic group (i.e., African American, Latino, and European American) and asthma status. The resulting p-values were meta-analyzed accounting for sample size and direction of effect. Top single nucleotide polymorphism (SNP) associations from the meta-analysis were reassessed in six additional cohorts comprising 5,767 individuals. Results We identified 10 unique regions where the combined association statistic was associated with total serum IgE levels (P-value <5.0×10−6) and the minor allele frequency was ≥5% in two or more population groups. Variant rs9469220, corresponding to HLA-DQB1, was the most significantly associated SNP with serum total IgE levels when assessed in both the replication cohorts and the discovery and replication sets combined (P-value = 0.007 and 2.45×10−7, respectively). In addition, findings from earlier GWA studies were also validated in the current meta-analysis. Conclusion This meta-analysis independently identified a variant near HLA-DQB1 as a predictor of total serum IgE in multiple race-ethnic groups. This study also extends and confirms the findings of earlier GWA analyses in African American and Latino individuals.

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Section: Methodsmentioning

confidence: 99%

A meta-analysis of genome-wide association studies for serum total IgE in diverse study populations

Levin

Mathias

Huang

et al. 2013

Journal of Allergy and Clinical Immunology

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“…In order to identify missense or nonsense (MS/NS) single-nucleotide variants (SNVs) associated with LVMHT we conducted a mixed model regression with LVMHT as the dependent variable controlling for kinship structures as well as age, sex, and weight as covariates using the kinship R package program LMEKIN (Lourenco et al, 2011). We used a false discovery rate (FDR) criterion of q -value <0.25 ( P -value <0.00258) for significance; this is more flexible than the usual Bonferroni criterion given our small sample size ( N = 21).…”

Section: Methodsmentioning

confidence: 99%

Whole-exome Sequencing and an iPSC-Derived Cardiomyocyte Model Provides a Powerful Platform for Gene Discovery in Left Ventricular Hypertrophy

Dai¹,

Irvin²,

Gu³

et al. 2012

Front. Gene.

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Rationale: Left ventricular hypertrophy (LVH) is a heritable predictor of cardiovascular disease, particularly in blacks. Objective: Determine the feasibility of combining evidence from two distinct but complementary experimental approaches to identify novel genetic predictors of increased LV mass. Methods: Whole-exome sequencing (WES) was conducted in seven African-American sibling trios ascertained on high average familial LV mass indexed to height (LVMHT) using Illumina HiSeq technology. Identified missense or nonsense (MS/NS) mutations were examined for association with LVMHT using linear mixed models adjusted for age, sex, body weight, and familial relationship. To functionally assess WES findings, human induced pluripotent stem cell-derived cardiomyocytes (induced pluripotent stem cell-CM) were stimulated to induce hypertrophy; mRNA sequencing (RNA-seq) was used to determine gene expression differences associated with hypertrophy onset. Statistically significant findings under both experimental approaches identified LVH candidate genes. Candidate genes were further prioritized by seven supportive criteria that included additional association tests (two criteria), regional linkage evidence in the larger HyperGEN cohort (one criterion), and publically available gene and variant based annotations (four criteria). Results: WES reads covered 91% of the target capture region (of size 37.2 MB) with an average coverage of 65×. WES identified 31,426 MS/NS mutations among the 21 individuals. A total of 295 MS/NS variants in 265 genes were associated with LVMHT with q-value <0.25. Of the 265 WES genes, 44 were differentially expressed (P < 0.05) in hypertrophied cells. Among the 44 candidate genes identified, 5, including HLA-B, HTT, MTSS1, SLC5A12, and THBS1, met 3 of 7 supporting criteria. THBS1 encodes an adhesive glycoprotein that promotes matrix preservation in pressure-overload LVH. THBS1 gene expression was 34% higher in hypertrophied cells (P = 0.0003) and a predicted conserved and damaging NS variant in exon 13 (A2099G) was significantly associated with LVHMT (P = 4 × 10−6). Conclusion: Combining evidence from cutting-edge genetic and cellular experiments can enable identification of novel LVH risk loci.

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“…For each station and parameter (12*4 = 48 combinations) the goodness of fit of discharge (m 3 /s) versus concentration (mg/L) was evaluated for six models: (1) linear (y = ax + b), (2) simple logarithmic (logy = ax + b), (3) double logarithmic (logy = a logx + b), (4) second degree polynomial (y = ax 2 + bx + c), (5) power (y = ax b ), and exponential (6) (y = ae bx ) (Malan, Bath, Day, & Joubert, ). In order to minimize the effect of extreme values, linear regression model fitting was done by the Iteratively Reweighted Least Squares procedure, with initial estimates of β and σ given by the LS estimate and the rescaled Median Aditive Deviation, respectively (Lourenco, Piers, & Kirst, ).…”

Section: Data Sources and Analysismentioning

confidence: 99%

Surface water quality in a sulfide mineral‐rich arid zone in North‐Central Chile: Learning from a complex past, addressing an uncertain future

Flores

Núñez

Oyarzún

et al. 2016

Hydrological Processes

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This study presents an analysis of up to 30 years of hydrological variables and selected water quality parameters (pH, SO4, Fe, Cu, and As) in the upper area of the Elqui River basin in North‐Central Chile. A correlation analysis determined statistically significant positive relationship for SO4‐Cu, Fe‐As, and Fe‐Cu. In terms of historical behaviour, no statistically significant trends were detected for precipitation or temperature. In contrast, for flow, there is an overall decreasing pattern for the entire area of study, although only in one case this trend was statistically significant. Along with the aforementioned analysis, a characterization of the flow‐water quality relationships is considered for the time period analyzed. Although erratic behaviours were confirmed, a negative (i.e., inverse) flow‐concentration relationship was identified for SO4, a positive (i.e., direct) relationship for Fe, and undefined relationships for As and Cu were obtained. From these analyses and based on previous studies on projections regarding climate change for the Andean region, and in particular for the upper Elqui zone, an estimation of the possible effects of the change in water regimes on water quality in the area of study is developed. It is likely that a decrease in surface flow, as a consequence of climate change could translate into improvements in water quality in terms of Fe and eventually As and Cu, but into an impairment in the case of SO4. In any case, this is a complex situation that demands special attention in the face of industrial activities that could be developed in tributaries like the Claro River, which currently play an important role in depurating or diluting contaminants in the waters of the Elqui River. Finally, it should be noted that this study addresses an issue that goes beyond the local interest and could be used as a reference to compare other transitional environments containing sulphide ores or areas of hydrothermal alterations, which are considered to be highly vulnerable to climate change and variability.

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Robust linear regression methods in association studies

Abstract: The code of the robustified version of function lmekin() from the R package kinship is provided as Supplementary Material.

Cited by 51 publications

References 42 publications

A meta-analysis of genome-wide association studies for serum total IgE in diverse study populations

A meta-analysis of genome-wide association studies for serum total IgE in diverse study populations

Whole-exome Sequencing and an iPSC-Derived Cardiomyocyte Model Provides a Powerful Platform for Gene Discovery in Left Ventricular Hypertrophy

Surface water quality in a sulfide mineral‐rich arid zone in North‐Central Chile: Learning from a complex past, addressing an uncertain future

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