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PubMed2000

Search for multifactorial disease susceptibility genes in founder populations.

The current challenge in biomedical research is to detect genetic risk factors involved in common complex diseases. The power to detect their role is generally poor in populations that have been large for a long time. It has been suggested that the power may be increased by taking advantage of the specificity of founder populations: linkage disequilibrium spanning larger regions and kinship coefficients being stronger than in large populations. A new method is proposed here, the Maximum Identity Length Contrast (MILC) which, in contrast with other existing methods, does not make the assumption of unique ancestry for the genetic risk factors. It is thus appropriate for a search for common genetic risk factors for complex diseases. Statistical properties of the method are discussed in realistic contexts.

Founder Effect↗
PubMed2000

The consistency of the posterior probability of linkage.

When searching for trait loci along the genome, properly incorporating prior genomic information into the analysis will almost certainly increase the chance of success. Recently, we devised a method that utilizes such prior information in the mapping of trait genes for complex disorders (Vieland, 1998; Wang el al. 1999; Vieland et al. 2000). This method uses the posterior probability of linkage (PPL) based on the admixture model as a measure of linkage information. In this paper, we study the consistency of the PPL. It is shown that, as the number of pedigrees increases, the PPL converges in probability to 1 when there is linkage between the marker and a trait locus, and converges to 0 otherwise. This conclusion is shown to be true for general pedigrees and trait models, even, when the likelihood functions are based on misspecified trait models. As part of the effort to prove this conclusion, it is shown that when there is no linkage, the maximum likelihood estimator of the recombination fraction in the admixture model is asymptotically 0.5, even when the admixture model misrepresents the true model.

Computer Simulation↗
PubMed2003

Genetic variation at the chromosome 16 chemokine gene cluster: development of a strategy for association studies in complex disease.

The chemokine gene cluster [CCL22, CX3CL1, CCL17] (previously known as [SCYA22, SCYD1, SCYA17]) is a candidate locus for one of the susceptibility genes for inflammatory bowel disease that are located in the peri-centromeric region of chromosome 16. Screening for sequence variation at this locus led to the detection of 14 single nucleotide polymorphisms (SNPs). An efficient experimental and computational approach was developed to estimate allele frequencies and pairwise linkage disequilibrium relationships between SNPs at this locus, and to test them for association with inflammatory bowel disease. The 12 common SNPs were assigned to 5 distinct linkage disequilibrium groups. Genotyping of one SNP from each linkage disequilibrium group in a large cohort of families with inflammatory bowel disease did not provide convincing evidence of association with either Crohn's disease or ulcerative colitis. We describe an efficient experimental design from SNP screening to association testing. This strategy can be used to test candidate genes for involvement in susceptibility to complex disease.

Chemokines↗
PubMed2004

Admixture in the Hispanics of the San Luis Valley, Colorado, and its implications for complex trait gene mapping.

Hispanic populations are a valuable resource that can and should facilitate the identification of complex trait genes by means of admixture mapping (AM). In this paper we focus on a particular Hispanic population living in the San Luis Valley (SLV) in Southern Colorado. We used a set of 22 Ancestry Informative Markers (AIMs) to describe the admixture process and dynamics in this population. AIMs are defined as genetic markers that exhibit allele frequency differences between parental populations >or=30%, and are more informative for studying admixed populations than random markers. The ancestral proportions of the SLV Hispanic population are estimated as 62.7 +/- 2.1% European, 34.1 +/- 1.9% Native American and 3.2 +/- 1.5% West African. We also estimated the ancestral proportions of individuals using these AIMs. Population structure was demonstrated by the excess association of unlinked markers, the correlation between estimates of admixture based on unlinked marker sets, and by a highly significant correlation between individual Native American ancestry and skin pigmentation (R2= 0.082, p < 0.001). We discuss the implications of these findings in disease gene mapping efforts.

Adult↗
PubMed2005

Genetic association studies in complex disease: disentangling additional predisposing loci from associated neutral loci using a constrained - permutation approach.

In the process of genetically mapping a complex disease, the question may arise whether a certain polymorphism is the only causal variant in a region. A number of methods can answer this question, but unfortunately these methods are optimal for bi-allelic loci only. We wanted to develop a method that is more suited for multi-allelic loci, such as microsatellite markers. We propose the Additional Disease Loci Test (ADLT): the alleles at an additional locus are permuted within the subsample of haplotypes that have identical alleles at the predisposing locus. The hypothesis being tested is, whether the predisposing locus is the sole factor predisposing to the trait that is in LD with the additional locus under study. We applied ADLT to simulated datasets and a published dataset on Type 1 Diabetes, genotyped for microsatellite markers in the HLA-region. The method showed the expected number of false-positive results in the absence of additional loci, but proved to be more powerful than existing methods in the presence of additional disease loci. ADLT was especially superior in datasets with less LD or with multiple predisposing alleles. We conclude that the ADLT can be useful in identifying additional disease loci.

Diabetes Mellitus, Type 1↗
PubMed2003

[Human molecular genetics: from monogenic to polygenic or complex disorders].

Human molecular genetics has successfully identified the genes involved in several monogenic disorders. It now aims at pinpointing the genetic determinants of polygenic or complex traits with a strong genetic component. This constitutes a new challenge. We discuss the methodological and practical aspects of identifying such genes as well as the challenges facing physicians that will have to use efficiently these new diagnostic tools.

Genetic Predisposition to Disease↗
PubMed2026

[Sex-specific depression risk].

Major depression displays significant heritability, and its genetic background has been extensively explored by genome-wide association studies. On the whole, these results indicate a highly polygenic landscape with significant sex-linked differences revealing a higher and more polygenic genetic influence in females than in males.

Humans↗
PubMed2002

[Molecular genetics of cholesterol cholelithiasis: identification of human and murine gallstone genes].

Cholesterol cholelithiasis is one of the most common gastroenterological diseases in Western countries. It is a polygenic disease resulting from disturbed biliary cholesterol homeostasis. Association studies identified six human gallstone candidate genes. Polymorphisms in the genes encoding the apolipoproteins B and E, phospholipid flippase ( ABCB4), cholesterol ester transfer protein ( CETP), cholesterol-7alpha-hydroxylase ( CYP7A1) and ileal bile acid transporter ( SLC10A2) are correlated with gallstone prevalence. Quantitative Trait Locus (QTL) analysis localises additional unknown gallstone genes in inbred mice. Based on the natural variation of cholesterol gallstone susceptibility among different inbred strains, 5 lithogenic ( Lith) loci have been identified. Hepatobiliary transporters (e. g. bile salt export pump Abcb11) and key proteins of the lipoprotein metabolism (e. g. hepatic lipase Lipc) could be established as creedal candidate genes for Lith loci. The rapid progress of mouse and human genome projects provides the basis for the analysis of orthologous human LITH genes in gallstone patients, which might offer new prospects for individual risk assessment and molecular targets for stone prevention.

Animals↗
PubMed2004

[New strategies in schizophrenia: impact of endophentotypes].

Despite the compelling evidence for a strong heritability of schizophrenia, the aetiology and genetic underpinnings of this disabling disease still remain unclear. Reasonable explanations for current problems in identifying candidate genes for schizophrenia are the complexity of its genetic background as well as the heterogeneity of the clinical appearance of this disease. For a higher efficiency in genetic investigations, a new approach came up which defines clinically distinct traits much more precisely: the so called endophenotype concept. Schizophrenic patients suffer from marked cognitive deficits. These deficits are closely related to the neurobiological basis of the disease, exhibit a high negative impact on clinical outcome, and may serve as endophenotypes for genetic studies. Identification of neurocognitive endopenotypes is usually performed in terms of a combination of neuropsychological tests and neurophysiological measurements. Thus, future genetic investigations as well as psychosocial and psychopharmacological therapy strategies will focus on the severity and potential therapeutic modification of cognitive deficits in order to improve psychosocial reintegration of schizophrenic patients in the long-term.

Arousal↗
PubMed2005

Modification of human hearing loss by plasma-membrane calcium pump PMCA2.

Five adult siblings presented with autosomal recessive sensorineural hearing loss: two had high-frequency loss, whereas the other three had severe-to-profound loss affecting all frequencies. Genetic evaluation revealed that a homozygous mutation in CDH23 (which encodes cadherin 23) caused the hearing loss in all five siblings and that a heterozygous, hypofunctional variant (V586M) in plasma-membrane calcium pump PMCA2, which is encoded by ATP2B2, was associated with increased loss in the three severely affected siblings. V586M was detected in two unrelated persons with increased sensorineural hearing loss, in the other caused by a mutation in MYO6 (which encodes myosin VI) in one and by noise exposure, suggesting that this variant may modify the severity of sensorineural hearing loss caused by a variety of factors.

Adult↗
PubMed2000

Polygenic resistance to mouse pulmonary adenomas.

Susceptibility to urethan-induced pulmonary adenomas (PA) in mice is under polygenic control. To analyze these traits in detail, we generated a set of recombinant inbred (RI) mouse strains, called SMXA, from an intercross between PA-susceptible A/J and resistant SM/J, and established a strain distribution pattern (SDP) table of 158 marker loci for SMXA RI strains. From the SDP table, it was possible to estimate the allele for 4 known PA susceptibility (Pas) loci in all members of SMXA RI strains. We compared combinations of Pas loci alleles with the data of number of PA induced by urethan. One of the RI strains, SMXA24, showed extremely low PA numbers, whereas they had the A/J-derived alleles at all 4 Pas loci. F1 hybrids of SMXA24 and A/J developed as few PA as SMXA24 on exposure to urethan. To confirm the hypothesis that SMXA24 has dominant PA resistance gene(s), we examined a backcross generation to A/J for multiplicity of PA. A preliminary genome scan followed by quantitative trait locus analysis revealed two resistance loci, one on mouse chromosome 11 (MMU11) (logarithm of odds [LOD] score 4.35) and another on MMU12 (LOD score 6.47). They were named Par1 and Par3, respectively. Both loci were epistatic to Pas1, the major susceptibility loci on MMU6. We next asked if such dominant resistance loci play some role in human lung cancer by studying possible loss of heterozygosity (LOH) at syntenic chromosomal segments in 79 human lung cancers, including 30 adenocarcinomas, 25 squamous cell carcinomas (SQ), and 24 small cell carcinomas (SCC). The map positions of Par1 and Par3 correspond to human 17q11-23 and 14q11-24. Of 30 adenocarcinomas, LOH was found in 53% at 17q and in 30% at 14q. For both SQ and SCC, LOH in 17q were about 10%, but LOH in 14q was about 30% to 42%. Therefore, a gene in 17q seemed to be selective for adenocarcinomas, probably at the level of the target cell. In contrast, another gene in 14q affected all 3 types of lung carcinomas, suggesting it is related to the progression of lung tumors in general. A comparative approach may provide useful information for understanding human cancers.

Adenocarcinoma↗
PubMed2006

Immunogenetics of pemphigus: an update.

Pemphigus are rare but informative models of organ-specific autoimmune diseases, resulting from the interplay of environmental, genetic and stochastic factors. There are many arguments to consider that pemphigus have a genetic basis involving, as many other autoimmune diseases, several different genes with additive or synergistic effects. So far, the unique strategy used to identify the contributive loci has been direct analysis of candidate genes through conventional case-control association studies. The major histocompatibility complex in particular the class II locus was demonstrated to be associated with pemphigus with a high rate of replicability. The progresses in the understanding of pemphigus physiopathology and the development of new molecular tools offer new perspectives to unveiled the genetic basis of this group of autoimmune blistering diseases, as shown by recent studies of candidate genes expressed at different levels of the autoimmune process.

Animals↗
PubMed2001

A pedigree of one family with delayed sleep phase syndrome.

The prevalence of delayed sleep phase syndrome (DSPS) has been estimated to be quite low. Although no genetic inheritance pattern has been described, it has been reported that close to 50% of DSPS patients have biological relatives with similar symptoms. A pedigree of one extended family with symptoms suggestive of DSPS has been identified. Morningness-eveningness questionnaires were administered to all first- and second-degree relatives of a proband identified with DSPS. A total of 51 (86%) questionnaires were returned, and 6 adult biological relatives of 27 (22%) showed a preference for eveningness, which is much higher than reported in the general population. Both the paternal and maternal branches contained affected individuals, suggesting the possibility of a bilineal mode of inheritance. While the trait did not obey simple Mendelian inheritance, the vertical patterns of transmission were consistent with either an autosomal dominant mode of inheritance with incomplete penetrance or a multifactorial mode of inheritance. These data provide some preliminary support to the notion that eveningness, and thus DSPS, may have a genetic component. The prevalence of symptoms suggestive of DSPS is higher in this family than reported in the general population. Case reports such as this support the utility of larger, more systematic studies. It is unclear whether this degree of familiarity is representative of that in the general population.

Adult↗
PubMedDate not supplied

Genetics of hypertension: lessons learnt from mendelian and polygenic syndromes.

This brief review discusses genetic and genomic aspects of hypertension. A special emphasis is given to currently available strategies for gene identifications, including studies of rare Mendelian hypertension, candidate gene evaluation, genome-wide scans and approaches based on the comparative genome analysis. We also discuss the growing potential for pharmacogenetic approaches and address briefly the issue of genetic testing in complex polygenic traits.

Genomics↗