Linkage Disequilibrium Studies Research Articles

The algorithm for Alzheimer risk assessment based on APOE promoter polymorphisms.

BackgroundOver the past two decades, the APOE gene and its polymorphisms have been among the most studied risk factors of Alzheimer disease (AD) development; yet, there are discrepancies between various studies regarding their impact. For this reason, the evaluation of the APOE genotype has not been included in the current European Federation of Neurological Societies guidelines for AD diagnosis and management. This aim of this study was to add to this discussion by assessing the possible influence of multiple polymorphisms in the promoter region of the APOE gene and genotypes of its allele E on the risk for dementia.MethodsWe performed a comprehensive analysis of APOE gene polymorphisms, assessed the detected genotypes and correlated molecular findings with serum apolipoprotein E concentrations. The study comprised 110 patients with AD and 110 age-matched healthy individuals from the Polish population.ResultsFour polymorphisms of the APOE gene had minor allele frequency exceeding 5 % and were included in the analysis: −491A/T (rs449647), −427T/C (rs769446), −219T/G (rs405509) in the promoter region and +113G/C (rs440446) in intron 1. A protective effect of the −219G allele on AD development was observed. Also, the −491T and −219G alleles were found to be underrepresented in the carriers of the APOE E4 variant. On the basis of the genotype and linkage disequilibrium studies, a relative score was attributed to given genotypes with respect to the estimated probability of their protective effects against AD, giving rise to the ‘preventive score’. This ‘preventive score’, based on the total sums of the relative scores, expresses the protective effect deriving from the synergistic action of individual single-nucleotide polymorphisms. The ‘preventive score’ was identified as an independent predictive factor.ConclusionsWe propose a novel, more complex approach to AD risk assessment based on the additive effect of multiple polymorphic loci within the APOE promoter region, which on their own may have too weak an impact to reach the level of significance. This has potentially practical implications, as it may help to improve the informative potential of APOE testing in a clinical setting. Subsequent studies of the proposed system in large, multi-ethnic cohorts are necessary for its validation and to assess its potential practical value for clinical applications.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-016-0187-9) contains supplementary material, which is available to authorized users.

Evaluation of Linkage Disequilibrium Pattern and Association Study on Seed Oil Content in Brassica napus Using ddRAD Sequencing.

High-density genetic markers are the prerequisite for understanding linkage disequilibrium (LD) and genome-wide association studies (GWASs) of complex traits in crops. To evaluate the LD pattern in oilseed rape, we sequenced a previous association panel containing 189 B. napus inbred lines using double-digested restriction-site associated DNA (ddRAD) and genotyped 19,327 RAD tags. A total of 15,921 RAD tags were assigned to a published genetic linkage map and the majority (71.1%) of these tags was uniquely mapped to the draft reference genome “Darmor-bzh.” The distance of LD decay was 1,214 kb across the genome at the background level (r2 = 0.26), with the distances of LD decay being 405 kb and 2,111 kb in the A and C subgenomes, respectively. A total of 361 haplotype blocks with length > 100 kb were identified in the entire genome. The association panel could be classified into two groups, P1 and P2, which are essentially consistent with the geographical origins of varieties. A large number of group-specific haplotypes were identified, reflecting that varieties in the P1 and P2 groups experienced distinct selection in breeding programs to adapt their different growth habitats. GWAS repeatedly detected two loci significantly associated with oil content of seeds based on the developed SNPs, suggesting that the high-density SNPs were useful for understanding the genetic determinants of complex traits in GWAS.

Leveling the Playing Field in Homozygosity Mapping Using Map Distances.

Studies of linkage disequilibrium (LD) and its variation in the genome are of central importance for understanding evolutionary history, population structure, and selective sweeps. Extreme forms of the latter may result in runs of homozygosity (ROH). In human gene mapping, long ROHs are the basis for homozygosity mapping (HM) with length measured in terms of Mb (106 base pairs physical distance). LD varies greatly over the human genome so that long ROHs tend to occur preferentially in regions of high LD and ROHs of the same length in different regions are not strictly comparable. Thus, in human gene mapping, LD appears as a confounder that needs to be taken into account in the interpretation of ROHs. The effect of varying LD can be mitigated by working on a scale of centimorgans (cM, genetic distance) instead of Mb. We demonstrate this effect for HapMap 3 data on chromosome 19 and show examples with different ROH lengths depending on whether physical or genetic lengths are used. These results suggest that HM should preferably be done on genetic rather than physical distances.

No Association Was Found Between MTHFR and MTHFD1 SNPs and Vitamin Levels in People with Increased and Normal Erythropoiesis, after Compulsory Flour Fortification with Folic Acid

Background The methylenetetrahydrofolate reductase (MTHFR) and methylenetetrahydrofolate dehydrogenase (MTHFD1) enzymes play important roles in the metabolism of folate. MTHFR catalyses the reduction of 5,10-methylene-tetrahydrofolate (5,10-methylene-THF) to 5-methyl-THF and present a crucial role in the regulation of available folate to homocysteine remethylation, in a cobalamin (Cbl) dependent reaction. MTHFD1 has three distinct enzymatic activities in folate metabolism: the conversion of THF to 10-formyl-THF; the reversible conversion of 10-formyl-THF to 5,10-methenyl-THF; and the conversion of 5,10-methenyl-THF to 5,10-methylene-THF. The two enzymes were related with DNA synthesis and single nucleotides polymorphisms (SNPs) in their genes have been associated with lower folate levels. People who have increased cellular duplication could be affected by low folate levels. Hereditary spherocytosis (HS) patients had an increased erythropoiesis and need more amounts of acid folic. In Brazil, HS patients are usually treated with 5mg/day of folic acid, the only formulation available. The use of folic acid by β-thalassemia heterozygotes (β-TH) subjects is not common, and depends of the individual clinical feature. Furthermore, in Brazil, HS patients and β-TH people have been exposed to food fortification (wheat and corn flours) with 150 µg of FA since 2004. The influences of variants of MTHFR and MTHFD1 SNPs in people with increased erythropoiesis, especially in HS patients, are not known.Objective The aim of the study was to evaluate the interaction between MTHFR c. 677C>T and c. 1298A>C and MTHFD1 c. 1958G>A SNPs and the use or not of FA supplementation in HS patients. It was also our objective to compare the folate and Cbl levels according to genotypes for MTHFR and MTHFD1 SNPs in β-TH subjects and their controls.Methods Twenty-five patients with HS, 49 β-TH subjects and 98 healthy people exposed to mandatory fortification of wheat and corn flours with FA were included in this study. Serum folate and Cbl were determined by microbiologic assays. Genomic DNA was extracted from whole blood using commercial kit. The genotypes for MTHFR c. 1298A>C and MTHFD1 c.1958G>A SNPs were determined by Real Time PCR using TaqMan assays. PCR-RFLP was used for genotyping MTHFR c. 677C>T SNP. Haplotype frequencies (MTHFR c. 677C>T and c. 1298 A>G) and the standardized disequilibrium coefficient (D’) for pair-wise linkage disequilibrium were assessed by the Expectation-Maximization (EM) algorism using the Haploview Software. We considered linkage disequilibrium when D’ ≥0.50. The study of linkage disequilibrium was performed by calculating the coefficient D’ of Lewontin.Results The frequencies of genotypes for MTHFR (c. 677C>T and c. 1298A>C) and MTHFD1 c. 1958G>A SNPs were similar in HS, β-TH and control groups (p>0.05). When genotypes were grouped according to the presence of the mutated allele (CC vs. CT+TT for MTHFR c. 677C>T, AA vs. AC+CC for MTHFR c. 1298A>C and GG vs. GA+AA for MTHFD1 c. 1958G>A), no differences were also found (p>0.05). The MTHFR c.677C>T and c. 1298A>C SNPs are in complete linkage disequilibrium (D’=1.0). Regarding the correlation coefficient between the two loci (r2), the value found in this analysis was equal to 0.169 in HS versus control group and 0.205 in β-TH versus control group. The haplotype CA, which is formed by the ancestral allele of MTHFR c. 677C>T and c. 1298A>C SNPs respectively, was more frequent in controls (41.9%) than in the β-TH group (28.1%). However, this finding was not observed in HS group comared with control group. No association was found between genotypes for MTHFR c. 677C>T and c. 1298A>C and MTHFD1 c. 1958G>A and alterations in folate and Cbl levels in three groups. ANCOVA was used for evaluating the interaction between the use of FA supplementation and MTHFR c.677C>T SNP on folate levels in HS patients. Only FA supplementation was associated with increased serum folate, and no associations were observed with MTHFR SNP or interaction between both.Conclusion The SNPs were not associated with reduced serum folate levels in the three groups studied. This finding suggests that FA flour fortification in β-TH and controls, as well as, the supplementation plus fortification in HS group, could offset the effect of variants of SNPs, especially for MTHFR c.677C>T. DisclosuresNo relevant conflicts of interest to declare.

DQB1*06:02-Associated Pathogenic Anti-Myelin Autoimmunity in Multiple Sclerosis-Like Disease: Potential Function of DQB1*06:02 as a Disease-Predisposing Allele.

Susceptibility to multiple sclerosis (MS) has been linked mainly to the HLA-DRB1 locus, with the HLA-DR15 haplotype (DRB1*1501-DQA1*0102-DQB1*0602-DRB5*0101) dominating MS risk in Caucasians. Although genes in the HLA-II region, particularly DRB1*1501, DQA1*0102-DQB1*0602, are in tight linkage disequilibrium, genome-wide-association, and gene candidate studies identified the DRB1*15:01 allele as the primary risk factor in MS. Many genetic and immune-functional studies have indicated DRB1*15:01 as a primary risk factor in MS, while only some functional studies suggested a disease-modifying role for the DRB5*01 or DQB1*06 alleles. In this respect, the susceptibility of DRB1*15:01-transgenic (Tg) mice to myelin basic protein- or myelin oligodendrocyte glycoprotein-induced MS-like disease is consistent with primary contribution of DRB1*15:01 to HLA-DR15+ MS. The studies summarized here show that susceptibility to MS-like disease, induced in HLA-“humanized” mice by myelin oligodendrocytic basic protein or by the proteolipid protein, one of the most prominent encephalitogenic target antigens implicated in human MS, is determined by DQB1*06:02, rather than by the DRB1*15:01 allele. These findings not only offer a rationale for a potential role for DQB1*06:02 in predisposing susceptibility to MS, but also suggest a more complex and differential functional role for HLA-DR15 alleles, depending on the primary target myelin antigen. However, the conflict between these findings in HLA-Tg mice and the extensive genome-wide-association studies, which could not detect any significant effect from the DQB1*06:02 allele on MS risk, is rather puzzling. Functional analysis of MS PBLs for DQB1*06:02-associated anti-myelin autoimmunity may indicate whether or not DQB1*06:02 is associated with MS pathogenesis.

An evaluation of a novel estimator of linkage disequilibrium

The analysis of systems involving many loci is important in population and quantitative genetics. An important problem is the study of linkage disequilibrium (LD), a concept relevant in genome-enabled prediction of quantitative traits and in exploration of marker-phenotype associations. This article introduces a new estimator of a LD parameter (ρ(2)) that is much easier to compute than a maximum likelihood (or Bayesian) estimate of a tetra-choric correlation. We examined the conjecture that the sampling distribution of the estimator of ρ(2) could be less frequency dependent than that of the estimator of r(2), a widely used metric for assessing LD. This was done via an empirical evaluation of LD in 806 Holstein-Friesian cattle using 771 single-nucleotide polymorphism (SNP) markers and of HapMap III data on 21,991 SNPs (chromosome 3) observed in 88 unrelated individuals from Tuscany. Also, 1600 haplotypes over a region of 1 Mb simulated under the coalescent were used to estimate LD using the two measures. Subsequently, a simulation study compared the new estimator with that of r(2) using several scenarios of LD and allelic frequencies. From these studies, it is concluded that ρ(2) provides a useful metric for the study of LD as the distribution of its estimator is less frequency dependent than that of the standard estimator of r(2).

Study of whole genome linkage disequilibrium in Nellore cattle

BackgroundKnowledge of the linkage disequilibrium (LD) between markers is important to establish the number of markers necessary for association studies and genomic selection. The objective of this study was to evaluate the extent of LD in Nellore cattle using a high density SNP panel and 795 genotyped steers.ResultsAfter data editing, 446,986 SNPs were used for the estimation of LD, comprising 2508.4 Mb of the genome. The mean distance between adjacent markers was 4.90 ± 2.89 kb. The minor allele frequency (MAF) was less than 0.20 in a considerable proportion of SNPs. The overall mean LD between marker pairs measured by r2 and |D'| was 0.17 and 0.52, respectively. The LD (r2) decreased with increasing physical distance between markers from 0.34 (1 kb) to 0.11 (100 kb). In contrast to this clear decrease of LD measured by r2, the changes in |D'| indicated a less pronounced decline of LD. Chromosomes BTA1, BTA27, BTA28 and BTA29 showed lower levels of LD at any distance between markers. Except for these four chromosomes, the level of LD (r2) was higher than 0.20 for markers separated by less than 20 kb. At distances < 3 kb, the level of LD was higher than 0.30. The LD (r2) between markers was higher when the MAF threshold was high (0.15), especially when the distance between markers was short.ConclusionsThe level of LD estimated for markers separated by less than 30 kb indicates that the High Density Bovine SNP BeadChip will likely be a suitable tool for prediction of genomic breeding values in Nellore cattle.

Patterns of Transcriptome Divergence in the Male Accessory Gland of Two Closely Related Species of Field Crickets

One of the central questions in evolutionary genetics is how much of the genome is involved in the early stages of divergence between populations, causing them to be reproductively isolated. In this article, we investigate genomic differentiation in a pair of closely related field crickets (Gryllus firmus and G. pennsylvanicus). These two species are the result of allopatric divergence and now interact along an extensive hybrid zone in eastern North America. Genes encoding seminal fluid proteins (SFPs) are often divergent between species, and it has been hypothesized that these proteins may play a key role in the origin and maintenance of reproductive isolation between diverging lineages. Hence, we chose to scan the accessory gland transcriptome to enable direct comparisons of differentiation for genes known to encode SFPs with differentiation in a much larger set of genes expressed in the same tissue. We have characterized differences in allele frequency between two populations for >6000 SNPs and >26,000 contigs. About 10% of all SNPs showed nearly fixed differences between the two species. Genes encoding SFPs did not have significantly elevated numbers of fixed SNPs per contig, nor did they seem to show larger differences than expected in their average allele frequencies. The distribution of allele frequency differences across the transcriptome is distinctly bimodal, but the relatively high proportion of fixed SNPs does not necessarily imply "ancient" divergence between these two lineages. Further studies of linkage disequilibrium and introgression across the hybrid zone are needed to direct our attention to those genome regions that are important for reproductive isolation.

Heat shock protein 70 polymorphism in hypertrophic cardiomyopathy of South Indian cohort

IntroductionHypertrophic cardiomyopathy is a disease of the myocardium inherited in an autosomal dominant mode of inheritance exhibiting clinical variability resulting in disease heterogeneity. Mutations in sarcomeric genes are implicated in the disease causation. Modifier genes and environmental factors are known to influence the phenotypic expression and severity of the disease. One such modifier gene is Heat shock protein-70 (HSP) which also acts as a molecular chaperon and its role in cardioprotection is also well established by inhibiting apoptosis, a manifestation of cardiac hypertrophy. The present study aims to elucidate the role of Hsp-70 polymorphisms viz: HSP 70-1/+190G/C, HSP 70-2/+1267A/G, HSP 70-hom/+2437T/C. Methods100 control samples and 100 HCM patients were genotyped for the 3 polymorphic regions of HSP 70: by PCR based RFLP analysis. ResultsA statistical significant association was observed in HSP 70-1/+190G/C and HSP 70-2/+1267A/G with the risk allele being ‘C’ and ‘G’ allele respectively. This was further substantiated by a stronger Linkage disequilibrium and secondary mRNA structure prediction studies, where ‘C’ allele of Hsp 70-1 was found to have a stable structure compared to the wild type. ConclusionsThe study clearly pinpoints to the role of heat shock proteins as modifiers in the inflammatory responses and hemodynamic compensatory mechanisms associated with HCM. The implication of Hsp in cardioprotection though well established seems to influence the progression and severity of the diseased phenotype by altered chaperoning, protein folding and regulation of transcription factors and ultimately apoptotic mechanisms associated with cardiac hypertrophy and remodeling in HCM.

Allelic variation in PtGA20Ox associates with growth and wood properties in Populus spp.

Populus tomentosa is an economically important tree crop that produces wood for lumber, pulp, paper, and biofuels. Wood quality traits are likely to be strongly affected by the plant hormone gibberellic acid (GA), which regulates growth. GA20Ox encodes one of the major regulatory enzymes of GA biosynthesis and may therefore play a large role in growth and wood quality. Here, linkage disequilibrium (LD) studies were used to identify significant associations between single nucleotide polymorphisms (SNPs) within PtGA20Ox and growth and wood-quality traits of P. tomentosa. We isolated a full-length GA20Ox cDNA from Populus tomentosa by reverse transcription (RT)-PCR; this 1401 bp cDNA clone had an open reading frame of 1158 bp and encoded a protein of 385 amino acids. PtGA20Ox transcripts were maximally expressed in the mature xylem of vascular tissues, suggesting that PtGA20Ox is highly expressed and specifically associated with secondary xylem formation. Resequencing the PtGA20Ox locus of 36 individuals identified 55 SNPs, and the frequency of SNPs was 1/31 bp. The 29 most common SNPs (frequency>0.1) were genotyped in an association population (426 individuals) that was also phenotyped for key growth and wood quality traits. LD did not extend over the entire gene (r 2<0.1, within 500 bp), demonstrating that a candidate-gene-based LD approach may the best way to understand the molecular basis underlying quantitative variation in this species. SNP- and haplotype-based association analyses indicated that four SNPs (false discovery rate Q<0.05) and 14 haplotypes (P<0.05) were significantly associated with growth and wood properties. The phenotypic variance explained by each SNP ranged from 3.44% to 14.47%. The SNP markers identified in this study can be applied to breeding programs for the improvement of growth and wood-property traits by marker-assisted selection.

Association between human leukocyte antigenand nasopharyngeal-carcinoma

Nasopharyngeal carcinoma (NPC) is characterized by its distinct racial and geographical distribution with a multifactorial etiology. It has been well accepted that NPC is related to Epstein-Barr(EB) virus infection but environmental and genetics factors also play critical roles. Among host genetic markers associated with NPC, the highly variable class I human leukocyte antigen (HLA) genes on chromosome 6 (6p21.3) have shown a strong and consistent association with NPC risk. As the consequence of new generation DNA sequencing technologies used in HLA genotyping, the number of the reported HLA new alleles is dramaticllyincreasing, and more full length sequences of HLA alleles have been reported. The significant association between HLA genes and NPC has been identifiedin a series of studies, including HLA association study, linkage disequilibrium study for microsatellite markers, and genome wide association study. In this review, we summarize association studies between HLA and NPC to evaluate the role of genetic polymorphisms in NPC development and illustrate the new clues of HLA association for deepexploration.

GWA Analysis for Milk Production Traits in Dairy Sheep and Genetic Support for a QTN Influencing Milk Protein Percentage in the LALBA Gene

In this study, we used the Illumina OvineSNP50 BeadChip to conduct a genome-wide association (GWA) analysis for milk production traits in dairy sheep by analyzing a commercial population of Spanish Churra sheep. The studied population consisted of a total of 1,681 Churra ewes belonging to 16 half-sib families with available records for milk yield (MY), milk protein and fat yields (PY and FY) and milk protein and fat contents (PP and FP). The most significant association identified reached experiment-wise significance for PP and FP and was located on chromosome 3 (OAR3). These results confirm the population-level segregation of a previously reported QTL affecting PP and suggest that this QTL has a significant pleiotropic effect on FP. Further associations were detected at the chromosome-wise significance level on 14 other chromosomal regions. The marker on OAR3 showing the highest significant association was located at the third intron of the alpha-lactalbumin (LALBA) gene, which is a functional and positional candidate underlying this association. Sequencing this gene in the 16 Churra rams of the studied resource population identified additional polymorphisms. One out of the 31 polymorphisms identified was located within the coding gene sequence (LALBA_g.242T>C) and was predicted to cause an amino acid change in the protein (Val27Ala). Different approaches, including GWA analysis, a combined linkage and linkage disequilibrium study and a concordance test with the QTL segregating status of the sires, were utilized to assess the role of this mutation as a putative QTN for the genetic effects detected on OAR3. Our results strongly support the polymorphism LALBA_g.242T>C as the most likely causal mutation of the studied OAR3 QTL affecting PP and FP, although we cannot rule out the possibility that this SNP is in perfect linkage disequilibrium with the true causal polymorphism.

Linkage disequilibrium decay and past population history in the human genome.

The fluctuation of population size has not been well studied in the previous studies of theoretical linkage disequilibrium (LD) expectation. In this study, an improved theoretical prediction of LD decay was derived to account for the effects of changes in effective population sizes. The equation was used to estimate effective population size (Ne) assuming a constant Ne and LD at equilibrium, and these Ne estimates implied the past changes of Ne for a certain number of generations until equilibrium, which differed based on recombination rate. As the influence of recent population history on the Ne estimates is larger than old population history, recent changes in population size can be inferred more accurately than old changes. The theoretical predictions based on this improved expression showed accurate agreement with the simulated values. When applied to human genome data, the detailed recent history of human populations was obtained. The inferred past population history of each population showed good correspondence with historical studies. Specifically, four populations (three African ancestries and one Mexican ancestry) showed population growth that was significantly less than that of other populations, and two populations originated from China showed prominent exponential growth. During the examination of overall LD decay in the human genome, a selection pressure on chromosome 14, the gephyrin gene, was observed in all populations.

The single nucleotide polymorphism and haplotype analysis of MDR1 in Jiangsu Han population of China

The aim of this study was to perform the frequency distribution of MDR1 gene SNPs and haplotypes of Jiangsu Han population in China. A total of 225 Jiangsu Han unrelated volunteers were enrolled and genotyped by PCR-ASP method at three loci: C1236T (rs1128503), G2677T/A (rs2032582) and C3435T (rs1045642). In total, C and T were found at locus 1236, with the frequency of 35% and 65%, respectively. The most frequent allele at locus 2677 was G with the frequency of 44%, followed by T (41%) and A (15%). At locus 3435, C was more common (60%) than T (40%). The most common haplotype at loci 1236-2677-3435 was T-T-T (31.84%), at loci 1236-2677 was T-T (37.68%), at loci 2677-3435 was G-C (39.06%), and at loci 1236-3435 was T-T (34.28%). The haplotype linkage disequilibrium study found that all three loci were in linkage disequilibrium, such as T-T at loci 1236-2677, T-T at loci 2677-3435 and C-C at loci 1236-3435 (P<0.01). The dendrogram study indicated that the distribution of MDR1 SNPs in Jiangsu Han population were close to Japan and Malay populations and far away from European countries. These findings could shade new lights in population genetics and anthropology studies of Han-Chinese. It also provides basic data for research on MDR1 gene polymorphism, disease association and drug resistance study.

Visualization of pairwise and multilocus linkage disequilibrium structure using latent forests.

Linkage disequilibrium study represents a major issue in statistical genetics as it plays a fundamental role in gene mapping and helps us to learn more about human history. The linkage disequilibrium complex structure makes its exploratory data analysis essential yet challenging. Visualization methods, such as the triangular heat map implemented in Haploview, provide simple and useful tools to help understand complex genetic patterns, but remain insufficient to fully describe them. Probabilistic graphical models have been widely recognized as a powerful formalism allowing a concise and accurate modeling of dependences between variables. In this paper, we propose a method for short-range, long-range and chromosome-wide linkage disequilibrium visualization using forests of hierarchical latent class models. Thanks to its hierarchical nature, our method is shown to provide a compact view of both pairwise and multilocus linkage disequilibrium spatial structures for the geneticist. Besides, a multilocus linkage disequilibrium measure has been designed to evaluate linkage disequilibrium in hierarchy clusters. To learn the proposed model, a new scalable algorithm is presented. It constrains the dependence scope, relying on physical positions, and is able to deal with more than one hundred thousand single nucleotide polymorphisms. The proposed algorithm is fast and does not require phase genotypic data.

Genetics of recurrent vertigo and vestibular disorders.

We present recent advances in the genetics of recurrent vertigo, including familial episodic ataxias, migraneous vertigo, bilateral vestibular hypofunction and Meniere’s disease.Although several vestibular disorders are more common within families, the genetics of vestibulopathies is largely not known. Genetic loci and clinical features of familial episodic ataxias have been defined in linkage disequilibrium studies with mutations in neuronal genes KCNA1 and CACNA1A. Migrainous vertigo is a clinical disorder with a high comorbidity within families much more common in females with overlapping features with episodic ataxia and migraine. Bilateral vestibular hypofunction is a heterogeneous clinical group defined by episodes of vertigo leading to progressive loss of vestibular function which also can include migraine. Meniere’s disease is a clinical syndrome characterized by spontaneous episodes of recurrent vertigo, sensorineural hearing loss, tinnitus and aural fullness and familial Meniere’s disease in around 10-20% of cases. An international collaborative effort to define the clinical phenotype and recruiting patients with migrainous vertigo and Meniere’s disease is ongoing for genome-wide association studies.

Abstract A88: Ancestry informative markers associated with prostate cancer in African Americans

Abstract Purpose: Prostate cancer (Pca) is the most common cancer in US males. African American men have higher incidence and mortality rates than do their European American counterparts. Five single nucleotide polymorphisms (SNPs) were found to be associated with Pca after analyzing data from a Pca mapping by admixture linkage disequilibrium (MALD) study using several different genetic models. The SNPs genotyped have significant allele frequency differences between African Americans and European Americans and are referred to as ancestry informative markers (AIMs). We tested the hypothesis that AIM haplotypes were also associated with Pca risk. Design Methods: AIM haplotypes were inferred for 98 Pca patients and 140 controls. Binary logistic regression was used to test haplotypes for association with Pca. Results: We found that haplotypes 5 “GTCCC,” 9 “ATTCT,” and 11 “ACCCC” were associated with Pca risk (OR = 3.97 95% CI: 1.68–9.47, p = 0.0017; OR = 7.17 95% CI: 2.33–20.05, p = 0.0006; OR = 3.68 95% CI: 1.57–8.62, p = 0.0027, respectively). After adjusting for age and ancestry all three haplotypes remained associated with Pca (OR = 3.62 95% CI: 1.42–9.21, p = 0.0070; OR = 7.89 95% CI: 2.36–26.31, p = 0.0008; OR = 4.34 95% CI: 1.75–10.78, p = 0.0016, respectively). We show that AIM haplotypes are associated with PCa risk. This study also demonstrates the use of a simple model to test for the additive or multiplicative effects of SNPs weakly associated individually. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A88.

Multilocus nuclear DNA markers and genetic parameters in an Indian Anopheles minimus population

Estimation of population genetic parameters is highly dependent on the choice of genetic markers. Furthermore, inferences based on single genes could lead to erroneous conclusions and population genetic outcomes, thus usage of multiple loci is suggested. Considering malaria is a highly fatal vector-borne infectious disease, inference on population genetic structure and demography could be of help in the long run for malaria vector management and control. Using the published genome sequence information of Anopheles gambiae we designed EPIC primers to amplify DNA fragments in An. minimus nuclear genome. Eight such DNA fragments could be successfully amplified and sequenced and homology to corresponding genes of An. gambiae was established. All the eight DNA fragments were found to be polymorphic for single nucleotide polymorphisms (SNPs) in a population sample of An. minimus from India. Several tests of neutrality confirmed that all the eight fragments evolve under a standard neutral model of molecular evolution. Furthermore, multilocus linkage disequilibrium studies revealed that the DNA fragments were not genetically linked to each other and thus are independently evolving. Tests of past population demographic events clearly revealed that this Indian population of An. minimus follows demographic equilibrium model, without any significant recent population bottleneck or expansion. The eight multilocus nuclear DNA fragments thus could be considered as ‘putatively neutral’ and be used to infer population structure and demographic history of An. minimus, a major malaria vector in the Southeast Asia and India. Moreover, the estimations of population demography using these putatively neutral markers can provide a baseline against which, test for the role of natural selection in functionally relevant genes of An. minimus would be possible.

Linkage disequilibrium organization of the human KIR superlocus: implications for KIR data analyses

An extensive family-based study of linkage disequilibrium (LD) in the killer cell immunoglobulin-like receptors (KIR) cluster was performed. We aimed to describe the LD structure in the KIR gene cluster using a sample of 418 founder haplotypes identified by segregation in a group of 106 families from Northern Ireland. The LD was studied at two levels of polymorphism: the structural level (presence or absence of KIR genes) and the allelic level (between alleles of KIR genes). LD was further assessed using the predictive value of one KIR polymorphism for another one in order to provide an interpretative framework for the LD effect in association studies. In line with previous research, distinct patterns of KIR genetic diversity within the genomic region centromeric to KIR2DL4 (excluding KIR2DL4) and within the telomeric region including KIR2DL4 were found. In a comprehensive PPV/NPV-based LD analysis within the KIR cluster, robust tag markers were found that can be used to identify which genes are concomitantly present or absent and to further identify groups of associated KIR alleles. Several extended KIR haplotypes in the study population were identified (KIR2DS2*POS–KIR2DL2*001–KIR2DL5B*002–KIR2DS3*00103–KIR2DL1*00401; KIR2DL4*011–KIR3DL1/S1*005–KIR2DS4*003–KIR3DL2*003; KIR2DL4*00802–KIR3DL1/S1*004–KIR2DS4*006–KIR3DL2*005; KIR2DL4*00801–KIR3DL1/S1*00101–KIR2DS4*003–KIR3DL2*001; KIR2DL4*00103–KIR3DL1/S1*008–KIR2DS4*003–KIR3DL2*009; KIR2DL4*00102–KIR3DL1/S1*01502/*002–KIR2DS4*00101–KIR3DL2*002; KIR2DL4*00501–KIR3DL1/S1*013–KIR2DL5A*001–KIR2DS5*002–KIR2DS1*002–KIR3DL2*007). The present study provides a rationale for analyzing associations of KIR polymorphisms by taking into account the complex LD structure of the KIR region.Electronic supplementary materialThe online version of this article (doi:10.1007/s00251-010-0478-4) contains supplementary material, which is available to authorized users.

Clinical hallmarks and genetic polymorphisms in the CFTR gene contribute to the disclosure of the A1006E mutation

Since the identification of the Cystic Fibrosis transmembrane conductance regulator (CFTR) gene in 1989, many genetic mutations have been found in cystic fibrosis (CF) patients. Dysfunctions of the CFTR gene are responsible for the highly variable clinical presentation ranging from severe CF, disseminated bronchiectasis, idiopathic chronic pancreatitis and congenital bilateral absence of vas deferens (CBAVD). Linkage disequilibrium studies have shown that some mutations are stringently coupled with polymorphisms in a genetic complex called haplotype. From a familial study of a patient with CBAVD, carrier of the A1006E mutation, we have observed its strict association with the polymorphism 5T-TG11. In order to speed up the genetic diagnosis and to correlate the clinical setting to this genetic feature, we have directly investigated the exon 17a, where the A1006E mutation is located, of five cystic fibrosis patients belonging to two unrelated families. All patients had the 5T-TG11 tract, F508del and one unknown mutation. One more family with two affected individuals carrying the Q220X/A1006E mutations was investigated for the poly-T polymorphism. All the members were found to have the A1006E mutation and the 5T-TG11 in the same DNA strand, demonstrating that this strategy is a reliable and inexpensive method for genotyping the CFTR gene. A detailed description of the clinical presentation and follow-up are provided in order to highlight common phenotypic features useful to improve the management of cystic fibrosis patients.