Secondary analyses for genome‐wide association studies using expression quantitative trait loci

Ngwa, Julius S.; Yanek, Lisa R.; Kammers, Kai; Kanchan, Kanika; Taub, Margaret A.; Scharpf, Robert B.; Faraday, Nauder; Becker, Lewis C.; Mathias, Rasika A.; Ruczinski, Ingo

doi:10.1002/gepi.22448

Cited by 3 publications

(2 citation statements)

References 71 publications

(98 reference statements)

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“… 39 PEAR1 encodes the platelet endothelial aggregation receptor 1, a transmembrane receptor highly expressed in platelets and endothelial cells. 40 Prior studies have reported associations between the rs12566888-G and the rs12041331-G variants in PEAR1 with increased platelet aggregation induced by adenosine diphosphate, 41 , 42 , 43 , 44 epinephrine, 41 and collagen. 42 , 45 Furthermore, our additional GWAS revealed time-dependent genetic effects of rs12566888-G on a faster increase in MPV (Longgang: β = 0.19; τ = 0.08340; P = 4.19 × 10 −9 ; and Baoan: β = 0.19; τ = 0.0836; P = 3.68 × 10 −10 ; supplemental Figures 22-24 ; supplemental Tables 12 , 28 , and 29 ), an indicator of platelet activation and turnover, during pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Genetic basis of pregnancy-associated decreased platelet counts and gestational thrombocytopenia

Yang,

Hu,

Zhen

et al. 2024

Blood

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Platelet counts reduction occurs throughout pregnancy, with 5-12% of pregnancies being diagnosed with gestational thrombocytopenia (GT), characterized by a decrease in platelet count during pregnancy. However, the underlying biological mechanism behind this altered platelet count phenomenon and GT remains unclear. Here, we utilized sequencing data from non-invasive prenatal test (NIPT) among 100,186 Chinese pregnancies and conducted the hitherto largest-scale genome-wide association studies (GWAS) on platelet counts at five periods of pregnancy (the first, second, and third trimesters, delivery, and the postpartum period), as well as two GT statuses (GT: platelet count < 150 × 109/L and severe GT: platelet count < 100 × 109/L). Our analysis revealed 138 genome-wide significant loci, explaining 10.4 to 12.1% of the observed variation. Attractively, we identified previously unknown changes in genetic effects on platelet counts during pregnancy for variants present in PEAR1 and CBL, with PEAR1 variants specifically associated with a faster decline in platelet counts. Furthermore, we found that variants present in PEAR1 and TUBB1 increased susceptibility to GT and severe GT. Our study provides the first insight into the genetic basis of platelet counts and GT in pregnancy, highlighting the critical role of PEAR1 in decreasing platelet counts during pregnancy and the occurrence of GT. Pregnancies carrying specific variants associated with declining platelet counts may experience a more pronounced decrease, thereby elevating the risk of GT. These findings lay the groundwork for further investigation into the biological mechanisms and causal implications of GT.

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Section: Discussionmentioning

confidence: 99%

Genetic basis of pregnancy-associated decreased platelet counts and gestational thrombocytopenia

Yang,

Hu,

Zhen

et al. 2024

Blood

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“…Chen et al (2011) was one of the first to recommend the use of GEE over variance component strategy in family‐based studies of dichotomous phenotypes. To our knowledge, both the LMM and the GEE approaches are more commonly used in GWAS of secondary phenotypes from extended pedigree data (Ngwa et al, 2022, Suktitipat et al, 2012). The focus of this study is on a dichotomous trait—the case–control status used to ascertain probands—and common markers.…”

Section: Discussionmentioning

confidence: 99%

Benchmarking statistical methods for analyzing parent–child dyads in genetic association studies

Ray

Vergara

Taub

et al. 2022

Genetic Epidemiology

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Genetic association studies of child health outcomes often employ family‐based study designs. One of the most popular family‐based designs is the case–parent trio design that considers the smallest possible nuclear family consisting of two parents and their affected child. This trio design is particularly advantageous for studying relatively rare disorders because it is less prone to type 1 error inflation due to population stratification compared to population‐based study designs (e.g., case–control studies). However, obtaining genetic data from both parents is difficult, from a practical perspective, and many large studies predominantly measure genetic variants in mother–child dyads. While some statistical methods for analyzing parent‐child dyad data (most commonly involving mother–child pairs) exist, it is not clear if they provide the same advantage as trio methods in protecting against population stratification, or if a specific dyad design (e.g., case–mother dyads vs. case–mother/control–mother dyads) is more advantageous. In this article, we review existing statistical methods for analyzing genome‐wide marker data on dyads and perform extensive simulation experiments to benchmark their type I errors and statistical power under different scenarios. We extend our evaluation to existing methods for analyzing a combination of case–parent trios and dyads together. We apply these methods on genotyped and imputed data from multiethnic mother–child pairs only, case–parent trios only or combinations of both dyads and trios from the Gene, Environment Association Studies consortium (GENEVA), where each family was ascertained through a child affected by nonsyndromic cleft lip with or without cleft palate. Results from the GENEVA study corroborate the findings from our simulation experiments. Finally, we provide recommendations for using statistical genetic association methods for dyads.

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Secondary analyses for genome‐wide association studies using expression quantitative trait loci

Ngwa

Yanek

Kammers

et al. 2022

Genetic Epidemiology

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Genome‐wide association studies (GWAS) have successfully identified thousands of single nucleotide polymorphisms (SNPs) associated with complex traits; however, the identified SNPs account for a fraction of trait heritability, and identifying the functional elements through which genetic variants exert their effects remains a challenge. Recent evidence suggests that SNPs associated with complex traits are more likely to be expression quantitative trait loci (eQTL). Thus, incorporating eQTL information can potentially improve power to detect causal variants missed by traditional GWAS approaches. Using genomic, transcriptomic, and platelet phenotype data from the Genetic Study of Atherosclerosis Risk family‐based study, we investigated the potential to detect novel genomic risk loci by incorporating information from eQTL in the relevant target tissues (i.e., platelets and megakaryocytes) using established statistical principles in a novel way. Permutation analyses were performed to obtain family‐wise error rates for eQTL associations, substantially lowering the genome‐wide significance threshold for SNP‐phenotype associations. In addition to confirming the well known association between PEAR1 and platelet aggregation, our eQTL‐focused approach identified a novel locus (rs1354034) and gene (ARHGEF3) not previously identified in a GWAS of platelet aggregation phenotypes. A colocalization analysis showed strong evidence for a functional role of this eQTL.

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Secondary analyses for genome‐wide association studies using expression quantitative trait loci

Cited by 3 publications

References 71 publications

Genetic basis of pregnancy-associated decreased platelet counts and gestational thrombocytopenia

Genetic basis of pregnancy-associated decreased platelet counts and gestational thrombocytopenia

Benchmarking statistical methods for analyzing parent–child dyads in genetic association studies

Secondary analyses for genome‐wide association studies using expression quantitative trait loci

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