A New Method for Detecting Significant p-values with Applications to Genetic Data

Vélez, Jorge Íván Bonilla; Correa, Juan Carlos; Arcos‐Burgos, Mauricio

doi:10.15446/rce.v37n1.44358

Cited by 18 publications

(20 citation statements)

References 15 publications

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“…Thus, the collection P 1 , P 2 ,…, P m of P -values were corrected for multiple testing using the false discovery rate (FDR) 35 and a method based on extreme-values theory. 36 Because hypotheses testing were of the same type, correction was only performed on the resulting m P -values. 35,36 For the single locus models, we estimated the Genomic Control “inflation factor” λ, to evaluate potential stratification effects.…”

Section: Methodsmentioning

confidence: 99%

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The PHF21B gene is associated with major depression and modulates the stress response

et al. 2016

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Major depressive disorder (MDD) affects around 350 million people worldwide, however the underlying genetic basis remains largely unknown. In this study, we took into account that MDD is a gene-environment disorder in which stress is a critical component, and used whole genome screening of functional variants to investigate the ‘missing heritability’ in MDD. GWAS analyses using single- and multi-locus linear mixed-effect models were performed in a Los Angeles Mexican-American cohort (196 controls, 203 MDD) and in a replication European-Ancestry cohort (499 controls, 473 MDD). Our analyses took into consideration the stress levels in the control populations. The Mexican-American controls, comprised primarily of recent immigrants, had high levels of stress due to acculturation issues and the European-Ancestry controls with high stress levels were given higher weights in our analysis. We identified 44 common and rare functional variants associated with mild to moderate MDD in the Mexican-American cohort (genome-wide FDR<0.05), and their pathway analysis revealed that the three top overrepresented GO processes were innate immune response, glutamate receptor signalling and detection of chemical stimulus in smell sensory perception. Rare variant analysis replicated the PHF21B gene in the ethnically unrelated European-Ancestry cohort. The TRPM2 gene, previously implicated in mood disorders, may also be considered replicated by our analyses. Whole genome sequencing analyses of a subset of the cohorts revealed that European-Ancestry individuals have a significantly reduced (50%) number of single nucleotide variants compared to Mexican-American individuals and for this reason the role of rare variants may vary across populations. PHF21b variants contribute significantly to differences in the levels of expression of this gene in several brain areas, including the hippocampus. Furthermore, using an animal model of stress, we found that Phf21b hippocampal gene expression is significantly decreased in animals resilient to chronic restraint stress, when compared to non-chronically stressed animals. Together, our results reveal that including stress level data enables the identification of novel rare functional variants associated with MDD.

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Section: Methodsmentioning

confidence: 99%

“…36 Because hypotheses testing were of the same type, correction was only performed on the resulting m P -values. 35,36 For the single locus models, we estimated the Genomic Control “inflation factor” λ, to evaluate potential stratification effects.…”

Section: Methodsmentioning

confidence: 99%

The PHF21B gene is associated with major depression and modulates the stress response

et al. 2016

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“…Variants significantly associated with the ADHD phenotype were determined after correction by multiple testing using the false discovery rate (FDR) (Benjamini and Hochberg ) and an alternative method based on extreme‐values theory (Vélez et al. ). As this is an attempt of evaluate an already known association, we have used the criterion of a P ‐value ≤0.10 to consider a positive replication.…”

Section: Methodsmentioning

confidence: 99%

ADGRL 3 ( LPHN 3) variants are associated with a refined phenotype of ADHD in the MTA study

Acosta

Swanson

Stehli

et al. 2016

Mol Genet Genomic Med

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Background ADHD is the most common neuropsychiatric condition affecting individuals of all ages. Long‐term outcomes of affected individuals and association with severe comorbidities as SUD or conduct disorders are the main concern. Genetic associations have been extensively described. Multiple studies show that intronic variants harbored in the ADGRL3 (LPHN3) gene are associated with ADHD, especially associated with poor outcomes.MethodsIn this study, we evaluated this association in the Multimodal Treatment Study of children with ADHD (MTA), initiated as a 14‐month randomized clinical trial of 579 children diagnosed with DSM‐IV ADHD‐Combined Type (ADHD‐C), that transitioned to a 16‐year prospective observational follow‐up, and 289 classmates added at the 2‐year assessment to serve as a local normative comparison group (LNCG). Diagnostic evaluations at entry were based on the Diagnostic Interview Schedule for Children‐Parent (DISC‐P), which was repeated at several points over the years. For an add‐on genetic study, blood samples were collected from 232 in the MTA group and 139 in the LNCG.ResultsFor the 205 MTA participants, 14.6% retained the DISC‐P diagnosis of ADHD‐C in adolescence. For 127 LNCG participants, 88.2% remained undiagnosed by the DISC‐P. We genotyped 15 polymorphic SNP markers harbored in the ADGRL3 gene, and compared allele frequencies for the 30 cases with continued diagnosis of ADHD‐C in adolescence to the other participants. Replication of the association of rs2345039 ADGRL3 variant was observed (P value = 0.004, FDR corrected = 0.03; Odds ratio = 2.25, upper CI 1.28–3.97).ConclusionThe detection of susceptibility conferred by ADGRL3 variants in the extreme phenotype of continued diagnosis of ADHD‐C from childhood to adolescence provides additional support that the association of ADGRL3 and ADHD is not spurious. Exploring genetic effects in longitudinal cohorts, in which refined, age‐dependent phenotypes are documented, is crucial to understand the natural history of ADHD.

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“…After the estimation process using the forward/ backward algorithm concluded, the estimated coefficientsβ 1 ; β 2 ; …;β m were extracted and a hypothesis test of the form H 0,i : β i = 0 vs. H 1,i : β i ≠ 0 was performed for the ith CEFVs to obtain the corresponding P value, P i (i = 1,2,…,m). The collection P 1 , P 2 ,…, P m was subsequently corrected for multiple testing using the false discovery rate (FDR) [31,32] using R [33].…”

Section: Gwas Analysis Of Common Variantsmentioning

confidence: 99%

Familial Alzheimer’s Disease and Recessive Modifiers

et al. 2019

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Alzheimer's disease (AD) is progressive brain disorder that affects~50 million people worldwide and has no current effective treatment. AD age of onset (ADAOO) has shown to be critical for the identification of genes that modify the appearance of AD signs and symptoms in a specific population. We clinically characterized and whole-exome genotyped 71 individuals with AD from the Paisa genetic isolate, segregating the (PSEN1) E280A dominant fully penetrant mutation, and analyzed the potential recessive effects of~50,000 common functional genomic variants to the ADAOO. Standard quality control and filtering procedures were applied, and recessive single-and multi-locus linear mixed-effects models were used. We identified genetic variants in the SLC9C1, CSN1S1, and LOXL4 acting recessively to delay ADAOO up to~11,~6, and~9 years on average, respectively. In contrast, the CC recessive genotype in marker DHRS4L2-rs2273946 accelerates ADAOO by~8 years. This study, reports new recessive variants modifying ADAOO in PSEN1 E280A mutation carriers. This set of genes are implicated in important biological processes and molecular functions commonly affected by genes associated with the etiology of AD such as APP, APOE, and CLU. Future functional studies using modern techniques such as induced pluripotent stem cells will allow a better understanding of the over expression and down regulation of these recessive modifier variants and hence the pathogenesis of AD. These results are important for prediction of AD and ultimately, substantial to develop new therapeutic strategies for individuals at risk or affected by AD.

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A New Method for Detecting Significant p-values with Applications to Genetic Data

Cited by 18 publications

References 15 publications

The PHF21B gene is associated with major depression and modulates the stress response

The PHF21B gene is associated with major depression and modulates the stress response

ADGRL 3 ( LPHN 3) variants are associated with a refined phenotype of ADHD in the MTA study

Familial Alzheimer’s Disease and Recessive Modifiers

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