Genome-wide association analyses of expression phenotypes

A number of issues arise when analyzing the large amount of data from high-throughput genotype and expression microarray experiments, including design and interpretation of genome-wide association studies of expression phenotypes. These issues were considered by contributions submitted to Group 1 of the Genetic Analysis Workshop 15 (GAW15), which focused on the association of quantitative expression data. These contributions evaluated diverse hypotheses, including those relevant to cancer and obesity research, and used various analytic techniques, many of which were derived from information theory. Several observations from these reports stand out. First, one needs to consider the genetic model of the trait of interest and carefully select which single nucleotide polymorphisms and individuals are included early in the design stage of a study. Second, by targeting specific pathways when analyzing genome-wide data, one can generate more interpretable results than agnostic approaches. Finally, for datasets with small sample sizes but a large number of features like the Genetic Analysis Workshop 15 dataset, machine learning approaches may be more practical than traditional parametric approaches.     

The unique characteristics of Thai Leber hereditary optic neuropathy: analysis of 30 G11778A pedigrees

Leber hereditary optic neuropathy (LHON) is characterized by acute or subacute bilateral visual loss, and affects mostly young males. The most common mitochondrial DNA mutation responsible for LHON worldwide is G11778A. Despite different genetic backgrounds, which are believed to influence the disease expression, most features of LHON are quite common in different populations. However, there seem to be a few ethnic-specific differences. Analyses of our 30 G11778A LHON pedigrees in Thailand showed some characteristics different from those of Caucasians and Japanese. In particular, our pedigrees showed a lower male to female ratio of affected persons (2.6:1) and much higher prevalence of G11778A blood heteroplasmy (37% of the pedigrees contained at least one heteroplasmic G11778A individual). Heteroplasmicity seemed to influence disease manifestation in our patients but did not appear to alter the onset of the disease. The estimated overall penetrance of our G11778A LHON population was 37% for males and 13% for females. When each of our large pedigrees were considered separately, disease penetration varied from 9 to 45% between the pedigrees, and also varied between different branches of the same large pedigree. Survival analysis showed that the secondary LHON mutations G3316A and C3497T had a synergistic deleterious effect with the G11778A mutation, accelerating the onset of the disease in our patients.     

A common variant in the CDKN2B gene on chromosome 9p21 protects against coronary artery disease in Americans of African ancestry

A 58 kb region on chromosome 9p21.3 has consistently shown strong association with coronary artery disease (CAD) in multiple genome-wide association studies in populations of European and East Asian ancestry. In this study, we sought to further characterize the role of genetic variants in 9p21.3 in African American individuals. Apparently healthy African American siblings (n = 548) of patients with documented CAD < 60 years of age were genotyped and followed for incident CAD for up to 17 years. Tests of association for 86 single-nucleotide polymorphisms (SNPs) across the 9p21.3 region in a generalized estimating equation logistic framework under an additive model adjusting for traditional risk factors, family, follow-up time and population stratification were performed. A single SNP within the CDKN2B gene met stringent criteria for statistical significance, including permutation-based evaluations. This variant, rs3217989, was common (minor allele (G) frequency 0.242), conveyed protection against CAD (odds ratio (OR) = 0.19, 95% confidence interval (CI): 0.07 to 0.50, P = 0.0008) and was replicated in a combined analysis of two additional case/control studies of prevalent CAD/MI in African Americans (n = 990, P = 0.024, OR = 0.779, 95% CI: 0.626-0.968). This is the first report of a CAD association signal in a population of African ancestry with a common variant within the CDKN2B gene, independent from previous findings in European and East Asian ancestry populations. The findings demonstrate a significant protective effect against incident CAD in African American siblings of persons with premature CAD, with replication in a combination of two additional African American cohorts.     

Proportion of 11778 mutant mitochondrial DNA and clinical expression in a thai population with leber hereditary optic neuropathy.

BACKGROUND: The proportion of mutant mtDNA in blood has been found to correlate with the frequency of visual loss in cases with mtDNA mutations associated with Leber hereditary optic neuropathy (LHON), especially in men. We sought to determine this correlation in a Thai population of LHON. METHODS: Densitometric quantification of blood mtDNA with the 11,778 LHON mutation in 137 symptomatic cases and their asymptomatic maternal relatives in 30 Asian pedigree families was performed. Asymptomatic maternal relatives under the age of 16 years were excluded. The visual outcome in symptomatic cases with homoplasmy and heteroplasmy was compared. RESULTS: Heteroplasmy was detected in eight (12.9%) symptomatic and 30 (40%) asymptomatic individuals. The quantification of blood mutant mtDNA in the eight symptomatic cases ranged from 44% to 93% (mean=75%). The visual outcome of the cases with heteroplasmy was not different from that of cases with homoplasmy. There was a correlation between the proportion of mutant mtDNA and the likelihood of visual loss. CONCLUSIONS: The prevalence of heteroplasmy among pedigrees of the 11,778 LHON mutation in Thailand was similar to that of other Asian populations and may be greater than in 11,778 LHON pedigrees from white backgrounds. The proportion of mutated mtDNA correlated with visual loss, but the effect of heteroplasmy on clinical expression seemed not to relate to gender.     

Mitochondrial DNA haplogroup distribution in pedigrees of Southeast Asian G11778A Leber hereditary optic neuropathy.

To investigate the association of mitochondrial DNA (mtDNA) haplogroups and Leber hereditary optic neuropathy (LHON) in the Southeast Asian population, mtDNA haplogroup determination was performed by high-resolution restriction fragment length polymorphism in 42 patients with LHON who were carrying the G11778A mutation and in control subjects drawn from a Thai urban population unaffected by LHON. The patients with LHON were of Thai, Thai-Chinese, and Indian origin. Three mtDNA haplogroups, M, B*, and B, were found in LHON patients in a frequency similar to that in control subjects. mtDNA haplogroup F was found in none of the patients with LHON but was the second most common haplogroup in control subjects. The G11778A mutation must have arisen in our population independently from the mutation in Caucasians. In contrast to Caucasians, no specific mtDNA haplotype was associated with the patients with LHON in the Southeast Asian population. The mitochondrial polymorphisms that modify the expression of LHON in Southeast Asians could not be identified in this study. The lack of haplogroup F in our patients with LHON may indicate the protective effect of this haplogroup in the expression of this disorder.     

Gene‐Gene Interaction Among WNT Genes for Oral Cleft in Trios

Genome‐wide association studies (GWAS) for nonsyndromic cleft lip with or without cleft palate (CL/P) have identified multiple genes as important in the etiology of this common birth defect. We performed a candidate gene/pathway analysis explicitly considering gene‐gene (G × G) interaction to further explore the etiology of CL/P. Animal models have shown the WNT signaling pathway plays an important role in mid‐facial development, and various genes in this pathway have been associated with nonsyndromic CL/P in previous studies. We propose a combined approach to search for possible G × G interactions using machine learning and regression‐based methods to test for interactions between genes in the WNT family, and between these genes and other genes identified by GWAS in case‐parent trios. Using this combined approach of regression‐based and machine learning methods in CL/P case‐parent trios, we found robust evidence of G × G interaction between markers in WNT5B and MAFB (empiric P‐values = 0.0076 among Asian trios and P‐values = 0.018 among European trios). Additional evidence for epistatic interaction between markers in WNT5A, IRF6, and C1orf107 was seen among Asian trios, and markers in the 8q24 region and WNT5B among European trios.