Clustering of haplotypes based on phylogeny: how good a strategy for association testing?

Haplotypes are now widely used in association studies between markers and disease susceptibility locus. However, when a large number of markers are considered, the number of possible haplotypes increases leading to two problems: an increased number of degrees of freedom that may result in a lack of power and the existence of rare haplotypes that may be difficult to take into account in the statistical analysis. In a recent paper, Durrant et al proposed a method, CLADHC, to group haplotypes based on distance matrices and showed that this could considerably increase the power of the association test as compared to either single-locus analysis or haplotype analysis without prior grouping.

Highly efficient access to strained bicyclic ketals via gold-catalyzed cycloisomerization of bis-homopropargylic diols.

A highly efficient gold-catalyzed cycloisomerization reaction of bis-homopropargylic diols is described. The cyclizations are conducted in the presence of either AuI or AuIII catalysts in MeOH at room temperature in a very short time. The reaction conditions are compatible with functional groups, such as n-butyl, phenyl, allyl, benzyl, and alcohol groups, leading to original strained dioxabicyclo[2.

On the use of haplotype phylogeny to detect disease susceptibility loci.

Background: The cladistic approach proposed by Templeton has been presented as promising for the study of the genetic factors involved in common diseases. This approach allows the joint study of multiple markers within a gene by considering haplotypes and grouping them in nested clades. The idea is to search for clades with an excess of cases as compared to the whole sample and to identify the mutations defining these clades as potential candidate disease susceptibility sites.

Complex trait mapping in isolated populations: Are specific statistical methods required?

In this paper, we review the statistical methods that can be used in isolated populations to map genes involved in complex diseases. Our intention is to highlight the fact that if the features of population isolates may help in the identification of susceptibility factors for complex traits, the choice and design of methods for statistical analysis in these populations deserve particular care. We show that methods designed for outbred samples are generally not appropriate for isolated populations and could lead to false conclusions.

ABCA2 is a strong genetic risk factor for early-onset Alzheimer's disease.

Recent epidemiological, biological and genetic data indicate a relationship between cholesterol and Alzheimer's disease (AD) including the association of polymorphisms of ABCA1 (a gene that is known to participate in cholesterol and phospholipid transport) with AD prevalence. Based on these data, we postulated that genetic variation in the related and brain-specific ABCA2 gene leads to increase risk of AD. A large case-control study was conducted where the sample was randomly divided into a hypothesis-testing sample (230 cases/286 controls) and a validation sample (210 cases/233 controls).

Coincidence of two genetic forms of Charcot-Marie-Tooth disease in a single family.

The authors report a family in which two affected first cousins had a severe demyelinating Charcot-Marie-Tooth disease (CMT) phenotype. One had related parents, and there were no other affected relatives, suggesting an autosomal recessive mode of inheritance. Molecular studies showed that a de novo duplication in 17p11.

Robustness of case-control studies of genetic factors to population stratification: magnitude of bias and type I error.

Case-control studies of genetic factors are prone to a special form of confounding called population stratification, whenever the existence of one or more subpopulations may lead to a false association, be it positive or negative. We quantify both the bias (in terms of confounding risk ratio) and the probability of false association (type I error) in the most unfavorable situation in which only one high-risk subpopulation is hidden within the studied population, considering different scenarios of population structuring and varying sample sizes. In accord with previous work, we find that the bias is likely to be small in most cases.

Handling missing values in population data: consequences for maximum likelihood estimation of haplotype frequencies.

Haplotype frequency estimation in population data is an important problem in genetics and different methods including expectation maximisation (EM) methods have been proposed. The statistical properties of EM methods have been extensively assessed for data sets with no missing values. When numerous markers and/or individuals are tested, however, it is likely that some genotypes will be missing.

Association studies in candidate genes: strategies to select SNPs to be tested.

Objective: When numerous single nucleotide polymorphisms (SNPs) have been identified in a candidate gene, a relevant and still unanswered question is to determine how many and which of these SNPs should be optimally tested to detect an association with the disease. Testing them all is expensive and often unnecessary. Alleles at different SNPs may be associated in the population because of the existence of linkage disequilibrium, so that knowing the alleles carried at one SNP could provide exact or partial knowledge of alleles carried at a second SNP.

Demonstration of a chaos generator with two time delays.

We demonstrate a chaos generator involving two time delays and two nonlinear functions. Dynamic behaviors are numerically and experimentally observed. The complexity of the dynamics is discussed in terms of Lyapunov exponents and dimensions.

No replication of the association between the Nicastrin gene and familial early-onset Alzheimer's disease.

Polymorphisms in the Nicastrin (NCSTN) gene have recently been associated with familial early-onset Alzheimer's disease (AD). The authors genotyped four NCTSN polymorphisms in a large cohort of 489 AD cases (including 158 sporadic early-onset AD cases and 95 familial early-onset AD cases) and 386 controls but failed to replicate the association between NCSTN haplotype B and AD.

Investigation of seven proposed regions of linkage in multiple sclerosis: an American and French collaborative study.

Multiple sclerosis (MS) is a demyelinating autoimmune disease with a strong yet complex genetic component. To date only the HLA-DR locus, and specifically the HLA-DR15 allele, has been identified and confirmed as influencing the risk of developing MS. Genomic screens on several datasets have been performed and have identified several chromosomal regions with interesting results, but none have yet been confirmed.

Genetic analysis of multiple sclerosis in Europeans: French data.

We report the results of a genome-wide screen for linkage disequilibrium (LD) in multiple sclerosis (MS) performed on 200 cases, 200 controls and 200 case-parent trios from France employing pooled DNA methodology. A total of 3510 microsatellite markers supplied through the GAMES collaborative were analysed and ranked according to their evidence for association. The most promising 117 markers were then followed up in a two-step validation process.

Intercellular adhesion molecule-1: a protective haplotype against multiple sclerosis.

Intercellular adhesion molecule-1 (ICAM-1) and its receptors are adhesion molecules that play a key role in the transmigration of inflammatory cells through the blood-brain barrier, one of the earliest events in multiple sclerosis (MS), which leads to demyelination in the central nervous system. To investigate the role of genes encoding ICAM-1 and its receptors, we used a strategy of genetic linkage and association in 439 case-parent MS families of French origin, well characterized according to HLA status and severity. We demonstrate that the genes encoding ICAM-1 receptors do not influence MS susceptibility or severity.

Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54.

Hypogonadotropic hypogonadism is defined as a deficiency of the pituitary secretion of follicle-stimulating hormone and luteinizing hormone, which results in the impairment of pubertal maturation and of reproductive function. In the absence of pituitary or hypothalamic anatomical lesions and of anosmia (Kallmann syndrome), hypogonadotropic hypogonadism is referred to as isolated hypogonadotropic hypogonadism (IHH). A limited number of IHH cases are due to loss-of-function mutations of the gonadotropin-releasing hormone receptor.

Estimation of the inbreeding coefficient through use of genomic data.

Many linkage studies are performed in inbred populations, either small isolated populations or large populations with a long tradition of marriages between relatives. In such populations, there exist very complex genealogies with unknown loops. Therefore, the true inbreeding coefficient of an individual is often unknown.

Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a genetic component. Until now, the more consistent association with the disease is found with the major histocompatibility complex, especially HLA-DRB1*1501-DQB1*0602 haplotype. In this report, we demonstrate the interaction of Cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4 [CD152]) gene with DRB1*15 haplotype in multiple sclerosis genetic susceptibility.

Testing linkage and gene x environment interaction: comparison of different affected sib-pair methods.

The aim of this study was to compare, under different models of gene-environment (G x E) interaction, the power to detect linkage and G x E interaction of different tests using affected sib-pairs. Methods considered were: 1) the maximum likelihood lod-score (MLS), based on the distribution of parental alleles identical by descent (IBD) in affected sibs; 2) the sum of the MLS (sMLS) calculated in affected sib-pairs with 2, 1, or 0 sibs exposed; 3) the predivided sample test (PST), which compares the IBD distribution between affected sib-pairs with 2, 1, or 0 sibs exposed; 4) the triangle test statistic (TTS), which uses the IBD distribution among discordant affected sib-pairs (one exposed, one unexposed); and 5) the mean interaction test (MIT), based on the regression of the proportion of alleles shared IBD among affected sib-pairs on the exposure among sib-pairs. The MLS, sMLS, and MIT allow detection of linkage.

Phospholipid fatty acids and sterols of two Cinachyrella sponges from the Saudi Arabian Red Sea: comparison with Cinachyrella species from other origins.

Phospholipid class compositions, fatty acids and sterols of the sponges Cinachyrella alloclada and C. kükenthali from the Saudi Arabian Red Sea were studied and compared with previous results for other Cinachyrella spp. collected in Senegal (East Atlantic) and New Caledonia (West Pacific).

A risk for early-onset Alzheimer's disease associated with the APBB1 gene (FE65) intron 13 polymorphism.

Alzheimer's disease (AD) is a genetically complex neurodegenerative disorder and the leading cause of dementia of the elderly. Recently, Hu et al. suggested that a trinucleotide deletion in intron 13 of the APBB1 gene was a factor protecting against late-onset AD.

Does accounting for gene-environment (GxE) interaction increase the power to detect the effect of a gene in a multifactorial disease?

Despite tremendous efforts, few genes involved in the susceptibility for complex disorders have been identified. One explanation is that these disorders are a result of an interaction between genes and environment, and under such conditions, it may be difficult to measure the true genetic effect without accounting for the interaction. Umbach and Weinberg ([2000] Am.

Deleterious genetic influence of CX3CR1 genotypes on HIV-1 disease progression.

We previously reported that patients homozygous for a specific mutation (M280) in the chemokine receptor CX3CR1 progressed to AIDS more rapidly than those with other genotypes. This deleterious effect would predict that a cohort of prevalent patients would be depleted in M280 carriers, because these patients would have disappeared before recruitment. This hypothesis is confirmed in this new study based on the French SEROCO cohort showing that patients homozygous for the M280 allele were rare among the seroprevalent group.

Impact of parental relationships in maximum lod score affected sib-pair method.

Many studies are done in small isolated populations and populations where marriages between relatives are encouraged. In this paper, we point out some problems with applying the maximum lod score (MLS) method (Risch, [1990] Am. J.