scholarly journals Tests of association based on genomic windows can lead to spurious associations when using genotype panels with heterogeneous SNP densities

2021 ◽  
Vol 53 (1) ◽  
Author(s):  
Jinghui Li ◽  
Zigui Wang ◽  
Rohan Fernando ◽  
Hao Cheng
Keyword(s):  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Tests Of Association ◽  
Snp Panels ◽  
Highly Correlated ◽  
Single Snps ◽  
Dense Single Nucleotide Polymorphism

AbstractDense single nucleotide polymorphism (SNP) panels are widely used for genome-wide association studies (GWAS). In these panels, SNPs within a genomic segment tend to be highly correlated. Thus, association studies based on testing the significance of single SNPs are not very effective, and genomic-window based tests have been proposed to address this problem. However, when the SNP density on the genotype panel is not homogeneous, genomic-window based tests can lead to the detection of spurious associations by declaring effects of genomic windows that explain a large proportion of genetic variance as significant. We propose two methods to solve this problem.

scholarly journals Replication of Top Loci From COL4A1/2 Associated With White Matter Hyperintensity Burden in Patients With Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (12) ◽  
pp. 3751-3755
Author(s):  
Jiang Li ◽  
Vida Abedi ◽  
Ramin Zand ◽  
Christoph J. Griessenauer ◽  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Ischemic Stroke ◽  
Odds Ratio ◽  
Association Studies ◽  
Genome Wide Association ◽  
White Matter Hyperintensity ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Genome Wide

Background and Purpose: The purpose of this study was to replicate the top loci associated with white matter hyperintensity (WMH) phenotypes identified by large genome-wide association studies and the loci identified from the previous candidate gene studies. Methods: A total of 946 Geisinger MyCode patients with acute ischemic stroke with validated European ancestry and magnetic resonance imaging data were included in this study. Log-transformed WMH volume, as a quantitative trait, was calculated by a fully automated quantification process. The genome-wide association studies was carried out by a linear mixed regression model (GEMMA). A candidate-single nucleotide polymorphism analysis by including known single nucleotide polymorphisms, reported from a meta-analysis and several large GWAS for WMH, was conducted in all cases and binary converted extreme cases. Results: No genome-wide significantly associated variants were identified. In a candidate-single nucleotide polymorphism study, rs9515201 ( COL4A2 ) and rs3744028 ( TRIM65 ), 2 known genetic loci, showed nominal or trend of association with the WMH volume (β=0.13 and P =0.001 for rs9515201; β=0.094 and P =0.094 for rs3744028), and replicated in a subset of extreme cases versus controls (odds ratio=1.78, P =7.74×10 − 4 for rs9515201; odds ratio=1.53, P =0.047 for rs3744028, respectively). MTHFR677 cytosine/thymine (rs1801133) also showed an association with the binary WMH with odds ratio=1.47 for T allele ( P =0.019). Conclusions: Replication of COL4A1/2 associated with WMH reassures that the genetic risk factors for monogenic and polygenic ischemic stroke are shared at gene level.

scholarly journals An Analysis Pipeline for Genome-wide Association Studies

2008 ◽  
Vol 6 ◽  
pp. CIN.S966 ◽  
Author(s):  
Stefan Stefanov ◽  
James Lautenberger ◽  
Bert Gold
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Missing Values ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Population Difference ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Genome Wide ◽  
And Control

We developed an efficient pipeline to analyze genome-wide association study single nucleotide polymorphism scan results. Perl scripts were used to convert genotypes called using the BRLMM algorithm into a modified PB format. We computed summary statistics characteristic of our case and control populations including allele counts, missing values, heterozygosity, measures of compliance with Hardy-Weinberg equilibrium, and several population difference statistics. In addition, we computed association tests, including exact tests of association for genotypes, alleles, the Cochran-Armitage linear trend test, and dominant, recessive, and overdominant models at every single nucleotide polymorphism (SNP). In addition, pairwise linkage disequilbrium statistics were elaborated, using the command line version of HaploView, which was possible by writing a reformatting script. Additional Perl scripts permit loading the results into a MySQL database conjoined with a Generic Genome Browser (gbrowse) for comprehensive visualization. This browser incorporates a download feature that provides actual case and control genotypes to users in associated genomic regions. Thus, re-analysis “on the fly” is possible for casual browser users from anywhere on the Internet.

scholarly journals Both variants of A1CF and BAZ1B genes are associated with gout susceptibility: a replication study and meta-analysis in a Japanese population

Human Cell ◽  
2021 ◽  
Vol 34 (2) ◽  
pp. 293-299
Author(s):  
Makoto Kawaguchi ◽  
Akiyoshi Nakayama ◽  
Yuka Aoyagi ◽  
Takahiro Nakamura ◽  
Seiko Shimizu ◽  
...  
Keyword(s):  
Japanese Population ◽  
Association Studies ◽  
Meta Analysis ◽  
Elevated Serum ◽  
Common Type ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Replication Studies ◽  
Genome Wide

AbstractGout is a common type of acute arthritis that results from elevated serum uric acid (SUA) levels. Recent genome-wide association studies (GWASs) have revealed several novel single nucleotide polymorphism (SNPs) associated with SUA levels. Of these, rs10821905 of A1CF and rs1178977 of BAZ1B showed the greatest and the second greatest significant effect size for increasing SUA level in the Japanese population, but their association with gout is not clear. We examined their association with gout using 1411 clinically-defined Japanese gout patients and 1285 controls, and meta-analyzed our previous gout GWAS data to investigate any association with gout. Replication studies revealed both SNPs to be significantly associated with gout (P = 0.0366, odds ratio [OR] with 95% confidence interval [CI]: 1.30 [1.02–1.68] for rs10821905 of A1CF, P = 6.49 × 10–3, OR with 95% CI: 1.29 [1.07–1.55] for rs1178977 of BAZ1B). Meta-analysis also revealed a significant association with gout in both SNPs (Pmeta = 3.16 × 10–4, OR with 95% CI: 1.39 [1.17–1.66] for rs10821905 of A1CF, Pmeta = 7.28 × 10–5, OR with 95% CI 1.32 [1.15–1.51] for rs1178977 of BAZ1B). This study shows the first known association between SNPs of A1CF, BAZ1B and clinically-defined gout cases in Japanese. Our results also suggest a shared physiological/pathophysiological background between several populations, including Japanese, for both SUA increase and gout susceptibility. Our findings will not only assist the elucidation of the pathophysiology of gout and hyperuricemia, but also suggest new molecular targets.

scholarly journals Correlation between Glucokinase Regulator (GCKR) Gene Polymorphisms and Serum Uric Acid Levels in Taiwanese Adolescents

2021 ◽  
Author(s):  
Li-Ju Ho ◽  
Chieh-Hua Lu ◽  
Ruei-Yu Su ◽  
Fu-Huang Lin ◽  
Sheng-Chiang Su ◽  
...  
Keyword(s):  
Uric Acid ◽  
Odds Ratio ◽  
Association Studies ◽  
Positive Association ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Adolescent Population ◽  
Genome Wide ◽  
Gckr Rs780094

Abstract Background: Recent genome-wide association studies revealed a positive association between hyperuricemia and variants of the glucokinase regulator (GCKR) gene in adults. This study replicated the genetic association in a Taiwanese adolescent population. Methods: The frequencies of different genotypes or alleles of the GCKR rs780094 and rs1260326 single-nucleotide polymorphism (SNP) were compared between 962 subjects (468 boys, 494 girls) with hyperuricemia (HUA) and normal uric acid (NUA) levels relative to gender. Logistic regression analysis was carried out to explore the genetic role in abnormal uric acid (UA) concentrations. Results: Boys had higher UA levels than girls (6.68 ± 0.06 and 5.23 ± 0.04 mg/dl, respectively, p < 0.001). The T allele had a higher HUA frequency than the C allele in both SNPs in girls; the rest of the frequencies of alleles and genotypes did not differentiate between subjects with HUA and NUA groups in both genders. However, after adjusting for confounding factors, the odds ratio for hyperuricemia incidence in TT genotype carriers was 1.75 (95% confidence interval [CI]: 1.02 to 3.00) and higher than the C-carrier genotype in rs1260326 of the girl population. Conclusion: The GCKR rs1260326 polymorphism is associated with higher UA concentrations in Taiwanese girl adolescents.

scholarly journals CACNA1C polymorphism and altered phosphorylation of tau in bipolar disorder

2016 ◽  
Vol 208 (2) ◽  
pp. 195-196 ◽  
Author(s):  
Joel Jakobsson ◽  
Erik Pålsson ◽  
Carl Sellgren ◽  
Frida Rydberg ◽  
Agneta Ekman ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphism ◽  
Case Control Studies ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Increased Risk ◽  
Causal Pathway ◽  
Neurochemical Marker

SummarySeveral genome-wide association studies and case–control studies have associated the single nucleotide polymorphism (SNP) rs1006737, situated in CACNA1C encoding the alpha 1C subunit of the L-type voltage-gated calcium channel, with bipolar disorder and other psychiatric disorders. However, the causal pathway linking genetic variants in CACNA1C with increased risk for developing brain disorders remains unclear. Here, we explored the association between the rs1006737 SNP and cerebrospinal fluid (CSF) markers. We found a significant association between the risk allele in rs1006737 and a decreased CSF hyperphosphorylated tau/total tau ratio in patients with bipolar disorder, thus linking variation in the CACNA1C gene to a neurochemical marker of neuroaxonal plasticity in those with this disorder.

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