Jing Cui

Power and type I error rate of false discovery rate approaches in genome-wide association studies

In genome-wide genetic studies with a large number of markers, balancing the type I error rate and power is a challenging issue. Recently proposed false discovery rate (FDR) approaches are promising solutions to this problem. Using the 100 simulated datasets of a genome-wide marker map spaced about 3 cM and phenotypes from the Genetic Analysis Workshop 14, we studied the type I error rate and power of Storeys FDR approach, and compared it to the traditional Bonferroni procedure. We confirmed that Storeys FDR approach had a strong control of FDR. We found that Storeys FDR approach only provided weak control of family-wise error rate (FWER). For these simulated datasets, Storeys FDR approach only had slightly higher power than the Bonferroni procedure. In conclusion, Storeys FDR approach is more powerful than the Bonferroni procedure if strong control of FDR or weak control of FWER is desired. Storeys FDR approach has little power advantage over the Bonferroni procedure if there is low linkage disequilibrium among the markers. Further evaluation of the type I error rate and power of the FDR approaches for higher linkage disequilibrium and for haplotype analyses is warranted.

Maternal influence on blood pressure suggests involvement of mitochondrial DNA in the pathogenesis of hypertension: the Framingham Heart Study.

Objective To investigate the contribution of the mitochondrial genome to hypertension and quantitative blood pressure (BP) phenotypes in the Framingham Heart Study cohort, a randomly ascertained, community-based sample. Methods Longitudinal BP values of 6421 participants (mean age, 53 years; 46% men) from 1593 extended families were used for analyses. In analyses of BP as a continuous trait, a variance components model with a variance component for maternal effects was used to estimate the mitochondrial heritability of the long-term average BP adjusted for age, sex, body mass index, and hypertension treatment. For analyses of BP as a categorical trait, a nonparametric test sensitive to excessive maternal inheritance was used to test for mitochondrial effect on long-term hypertension, defined as systolic BP of at least 140 mmHg or diastolic BP of at least 90 mmHg or use of antihypertensive medication in one-half or more of qualifying examinations. This test was based on 353 pedigrees comprised of 403 individuals informative for mitochondrial DNA contribution. Results The estimated fraction of hypertensive pedigrees potentially due to mitochondrial effects was 35.2% (95% confidence interval, 27–43%, P < 10−10). The mitochondrial heritabilities for multivariable-adjusted long-term average systolic BP and diastolic BP were, respectively, 5% (P < 0.02) and 4% (P = 0.11). Conclusion Our data provide support for a maternal effect on hypertension status and quantitative systolic BP, consistent with mitochondrial influence. Additional studies are warranted to identify mitochondrial DNA variant(s) affecting BP.

Polymorphisms in the Promoter Region of Catalase Gene and Essential Hypertension

Genetic variations that predispose individuals to complex disorders, such as essential hypertension, may be found in gene coding regions, intronic regions or in gene promoter regions. Most studies have focused on gene variations that result in amino acid substitutions because they result in different isoforms of the protein, presumably resulting in differences in protein properties. Less attention has been placed on the role of intronic or promoter mutations. In this report, we examined two single nucleotide polymorphisms (SNPs) in the catalase (CAT) gene prompter region in a cohort of hypertensive Caucasians and African Americans with a Mass Spec based Homogenous MassEXTEND assay. We found an association when a specific combination of the two promoter SNPs was examined in Caucasians. No association was observed in African Americans. Our data suggest that genetic variations in the promoter region of catalase gene influence the susceptibility to essential hypertension. In addition, the genetic factors that contribute to hypertension maybe different between ethnic groups.

A Novel Class of Tests for the Detection of Mitochondrial DNA–Mutation Involvement in Diseases

We develop a novel class of tests to detect mitochondrial DNA (mtDNA)-mutation involvement in complex diseases by the study of affected pedigree members. For a pedigree, affected individuals are first considered and are then connected through their relatives. We construct a reduced pedigree from an original pedigree. Each configuration of a reduced pedigree is given a score, with high scores given to configurations that are consistent with mtDNA-mutation involvement and low scores given to configurations that are not consistent with mtDNA-mutation involvement. For many pedigrees, the weighted sum of scores of the pedigrees is calculated. The tests are formed by comparing the observed score with the expected score under the null hypothesis that only nuclear autosomal mutations are involved. We study the optimality of score functions and weights under the heterogeneity model without phenocopies. We also develop a method to estimate the contribution that mtDNA mutations make if they are involved under a heterogeneity model. Finally, we apply our methods to three data sets: Leber hereditary optic neuropathy, a disease that has been proved to be caused by mtDNA mutations; non-insulin-dependent diabetes mellitus (NIDDM); and hypertension (HTN). We find evidence of mtDNA-mutation involvement in all three diseases. The estimated fraction of patients with NIDDM due to mtDNA-mutation involvement is 22% (95% confidence interval [CI] 6%-38%). The fraction of patients with HTN potentially due to mtDNA-mutation involvement is estimated at 55% (95% CI 45%-65%).

Genetic Variants of WNK4 in Whites and African Americans With Hypertension

Abstract— Human chromosome 17q has been implicated to contain a gene that influences hypertension susceptibility. This region contains the WNK4 gene that causes the mendelian disorder pseudohypoaldosteronism type II, characterized by high potassium levels and hypertension. The goal of this study was to identify genetic variants in all exons of WNK4 in hypertensive individuals and to examine the association of these variants with essential hypertension. Single‐nucleotide polymorphims (SNPs) were identified by sequencing the entire coding region in 32 whites and 32 African Americans with hypertension. A single SNP in whites and 8 SNPs in African Americans were genotyped in a larger cohort of whites (165 hypertensives; 91 normotensives) and African Americans (120 hypertensives; 98 normotensives). The frequency of the rare allele differed significantly between hypertensive whites (13.0%) and normotensive whites (7.1%, P =0.040) for the single intronic SNP (bp 1 156 666). This difference remained significant after adjusting for body mass index and sex (P =0.035). Genotypic frequencies differed significantly between hypertensive and normotensive individuals when a dominant model either with (P =0.027) or without (P =0.028) covariate adjustment was assumed. The odds ratio for hypertension was 2.28 for AA or AG individuals vs those with the GG genotype (95% confidence interval, 1.09 to 4.75). No significant differences in allelic or genotypic frequencies were observed in African Americans for any SNPs. The finding in whites is consistent with the hypothesis that polymorphisms in WNK4 influence the risk of hypertension. However, because the associated SNP does not appear to be a functional variant and the limitations of case/control association studies, confirmation of these results in additional cohorts is warranted.

Sequence variation of bradykinin receptors B1 and B2 and association with hypertension.

Objective To identify variants in the complete genomic sequence of the two subtypes of bradykinin receptors: B1 (BDKRB1) and B2 (BDKRB2) and to examine the association of these variants with essential hypertension. Design A case–control design comparing hypertensive and normotensive individuals was used. Method A 64.4 kb genomic region containing the BDKRB1 and BDKRB2 genes was sequenced in 30 African-American individuals. A total of 282 single-nucleotide polymorphisms (SNPs) were identified. A total of 21 SNPs were genotyped in our complete cohorts of hypertensive and normotensive African-Americans (n = 218), American-Caucasians (n = 220) and Greek-Caucasians (n = 194). Pair-wise correlation coefficients were computed to assess linkage disequilibrium (LD) patterns among the SNPs. Chi-squared tests and logistic regression were used to assess association between the SNPs and hypertension status. Result Pairwise LD demonstrated a general pattern of decline with increasing distance, which was consistent among the three groups with less LD in African-Americans. One SNP in the promoter region of BDKRB2 (rs1799722) was associated with hypertension (P = 0.044) in African-Americans. One SNP in BDKRB2 and three SNPs in BDKRB1 were associated with hypertension (P-values between 0.026 and 0.0004) in American-Caucasians. Haplotypes including those four SNPs and one SNP in B2, which results in an amino acid change, demonstrated a significant haplotype frequency difference between hypertensive and normotensive American-Caucasians (P = 0.025). Conclusion These results support the hypothesis that the African-American population is an older population compared with the other samples and the two bradykinin receptors may play a role in blood pressure regulation.

Sepiapterin reductase expression is increased in Parkinson’s disease brain tissue.

The PARK3 locus on chromosome 2p13 has shown linkage to both the development and age of onset of Parkinsons disease (PD). One candidate gene at this locus is sepiapterin reductase (SPR). Sepiapterin reductase catalyzes the final step in the biosynthetic pathway of tetrahydrobiopterin (BH(4)), an essential cofactor for aromatic amino acid hydrolases including tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. The expression of SPR was assayed using semiquantitative real-time RT-PCR in human post-mortem cerebellar tissue from neuropathologically confirmed PD cases and neurologically normal controls. The expression of other enzymes involved in BH(4) biosynthesis, including aldose reductase (AKR1B1), carbonyl reductase (CBR1 and CBR3), GTP-cyclohydrolase I (GCH1), and 6-pyruvoyltetrahydrobiopterin (PTS), was also examined. Single-nucleotide polymorphisms around the SPR gene that have been previously reported to show association to PD affection and onset age were genotyped in these samples. Expression of SPR showed a significant 4-fold increase in PD cases relative to controls, while the expression of AKR1B1 and PTS was significantly decreased in PD cases. No difference in expression was detected for CBR1, CBR3, and GCH1. Genetic variants did not show a significant effect on SPR expression, however, this is likely due to the low frequency of rare genotypes in the sample. While the association of SPR to PD is not strong enough to support that this is the PARK3 gene, this study further implicates a role for SPR in idiopathic PD.

Genetic analyses of longitudinal phenotype data: a comparison of univariate methods and a multivariate approach

BackgroundWe explored three approaches to heritability and linkage analyses of longitudinal total cholesterol levels (CHOL) in the Genetic Analysis Workshop 13 simulated data without knowing the answers. The first two were univariate approaches and used 1) baseline measure at exam one or 2) summary measures such as mean and slope from multiple exams. The third method was a multivariate approach that directly models multiple measurements on a subject. A variance components model (SOLAR) was employed in the univariate approaches. A mixed regression model with polynomials was employed in the multivariate approach and implemented in SAS/IML.ResultsUsing the baseline measure at exam 1, we detected all baseline or slope genes contributing a substantial amount (0.08) of variance (LOD > 3). Compared to the baseline measure, the mean measures yielded slightly higher LOD at the slope genes, and a lower LOD at the baseline genes. The slope measure produced a somewhat lower LOD for the slope gene than did the mean measure. Descriptive information on the pattern of changes in gene effects with age was estimated for three linked loci by the third approach.ConclusionWe found simple univariate methods may be effective to detect genes affecting longitudinal phenotypes but may not fully reveal temporal trends in gene effects. The relative efficiency of the univariate methods to detect genes depends heavily on the underlying model. Compared with the univariate approaches, the multivariate approach provided more information on temporal trends in gene effects at the cost of more complicated modelling and more intense computations.

Impact of non-ignorable missingness on genetic tests of linkage and/or association using case-parent trios

The transmission/disequilibrium test was introduced to test for linkage disequilibrium between a marker and a putative disease locus using case-parent trios. However, parental genotypes may be incomplete in such a study. When parental information is non-randomly missing, due, for example, to death from the disease under study, the impact on type I error and power under dominant and recessive disease models has been reported. In this paper, we examine non-ignorable missingness by assigning missing values to the genotypes of affected parents. We used unrelated case-parent trios in the Genetic Analysis Workshop 14 simulated data for the Danacaa population. Our computer simulations revealed that the type I error of these tests using incomplete trios was not inflated over the nominal level under either recessive or dominant disease models. However, the power of these tests appears to be inflated over the complete information case due to an excess of heterozygous parents in dyads.