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At least 1,621 records · Page 90Linked to original sources
PubMed2006

Why do young women smoke? II. Role of traumatic life experience, psychological characteristics and serotonergic genes.

Cigarette smoking is a complex behavioral phenotype to which environmental, psychological and genetic factors contribute. The purpose of this study was to investigate these multifactorial effects with a specific focus on young women and on genes that encode serotonin (5-HT) receptors and the 5-HT transporter. A case-control sample of female Israeli college students provided comprehensive background data and details of cigarette smoking and completed a battery of psychological instruments. They were divided into smoking initiators (SI, n=242) or non-initiators (NI, n=148); SI were further subdivided into high (HND, n=127) and low nicotine-dependent smokers (LND, n=115) on the basis of their scores on the Fagerstrom Tolerance Questionnaire (FTQ). Single-nucleotide polymorphisms (SNPs) in five serotonin receptor genes (HTR1A, HTR1B, HTR2A, HTR2C and HTR6) and the 5-HT transporter-linked polymorphic region (5-HTTLPR) were genotyped. In a logistic regression model for SI (chi2=117.90, P=1.6 x 10(-19), Nagelkerke R2=0.42), novelty seeking (odds ratio (OR)=1.134, P=0.00009) was a significant risk factor. A five SNP CACCC haplotype in HTR6 was a strong protective factor against SI (OR=0.26; P=0.007). The interaction of HTR6-C276T genotype and lifetime traumatic experience contributed strongly to the risk of SI (OR=13.88, P=0.0001). Specifically, subjects homozygous for the HTR6-C276T C allele showed significantly increased risk of SI if they had experienced trauma. Although significant (chi2=42.85, P=1.00 x 10(-7)), the best-fitting model for ND was less predictive than the model for SI (Nagelkerke R2=0.24). HTR1B-G861C GG genotype (OR=2.29, P=0.01) was a significant risk factor for HND. Further studies should consider the interactive contribution of life events and relevant gene variants to cigarette smoking and other complex behavioral traits.

Adult↗
PubMed2003

Functional implications of genetic variation in non-coding DNA for disease susceptibility and gene regulation.

The role of host genetic variation in determining susceptibility to complex disease traits is the subject of much research effort, but it often remains unclear whether disease-associated genetic polymorphisms are themselves functionally relevant or acting only as markers within an extended haplotype. Experimental approaches to investigate the functional impact of polymorphisms in non-coding regulatory DNA sequences for gene expression are discussed, including the role of gel-shift assays, DNA footprinting and reporter gene analysis. The limitations of different experimental approaches are presented together with future prospects for in vivo analysis. The strategic application of these functional approaches is discussed and illustrated by analysis of the role of genetic variation in the tumour necrosis factor promoter region in determining susceptibility to severe malaria.

DNA↗
PubMed2001

The genetics of essential hypertension.

Essential hypertension is an escalating problem for industrialized populations. It is currently seen as a 'complex' genetic trait caused by multiple susceptibility genes the effects of which are modulated by gene-environment and gene-gene interactions. Nevertheless, the success to date in identifying these susceptibility genes has been very limited. A number of candidates has been proposed, but demonstrating consistently the linkage or association with hypertension has been problematic. The data for angiotensinogen is undoubtedly the most extensive and meta-analysis has confirmed a significant association overall, although the risk contributed by this gene appears to be modest (odds ratio of 1.2). Identifying further genes - probably conferring even smaller attributable risks - represents a major challenge for future developments in this area. This contrasts markedly with the success that has been achieved in the past 5 years in solving the molecular genetics of a number of rare familial hypertension syndromes. The true incidences of some of these disorders may be higher than first appreciated, but it is still unclear if the genes for these syndromes also play a part in essential hypertension. A more complete understanding of the genetic basis of essential hypertension should be possible in the coming years using new strategies that take advantage of the information provided by the human genome project. This knowledge will irrevocably change the way we approach this disease in terms of its diagnosis, risk assessment for end-points such as stroke and heart disease, and the customised treatment that might be offered in the future.

Animals↗
PubMed1998

Cloning and chromosomal mapping of the murine norepinephrine transporter.

The norepinephrine (NE) transporter (NET), a target of many clinically prescribed antidepressants, regulates noradrenergic neurotransmission by efficiently clearing NE from synaptic spaces after release. To advance our understanding of NET gene structure, regulation, and potential associations with complex behavioral trait loci, we amplified a mouse norepinephrine transporter (mNET) cDNA from placenta total RNA and utilized mNET probes to isolate and characterize the mNET gene. Inferred translation of the major open reading frame of the mNET cDNA predicts a 617-amino acid protein with 12 putative membrane-spanning regions and 94% identity to human NET. The coding exons of the mNET cDNA were found to be spread across >36 kb of 129/Svj genomic DNA, with exon-intron boundaries bearing consensus gt/ag splice sites. Sequence upstream (202 bp) of the inferred translation initiation site matched the sequence of 5' rapid amplification of cDNA ends products from brain mRNA with no evidence for intervening introns and is preceded by a TATA box and canonical transcriptional regulatory elements that may play a role in mNET expression in vivo. Probes derived from mNET cDNA identified species-specific MspI restriction fragment length variations within the mNET gene that were utilized to position the gene (Slc6a5) to murine chromosome 8, one recombinant distal to D8Mit15. This site is within a recently defined quantitative trait locus defined for ethanol sensitivity in LSXSS recombinant inbred mice, Lore4. The status of Slc6a5 as a candidate gene for alcohol sensitivity is discussed with respect to studies noting ethanol-induced alterations in brain NE receptors, NE receptor-linked adenylate cyclase, and NE transport.

Amino Acid Sequence↗
PubMed2004

[Applications of congenic strains in the mouse].

The sequencing of the human and the mouse genomes has shown that the chromosomes of these two species contain approximately 30,000 genes. The biological systems that can be studied in an individual or in a tissue result from complex interactions within this multitude of genes. Before describing these interactions, it is necessary to understand the function of each gene. In the mouse, congenic strains are developed to introduce a chromosomal segment in a given inbred genetic background. One can then compare the biological effects of different alleles at the same locus in the same genetic background or the effect of a given allele in different genetic backgrounds. One can also introduce into different congenic strains with the same genetic background genes which control a complex genetic trait, then combine these genes by appropriate crosses to study their interactions. Although the chromosomal segment transferred into a congenic strain usually contains up to several hundreds of genes, molecular markers can be used to reduce this number as well as the number of crosses required for the development of congenic strains.

Animals↗
PubMed2002

Epidemiology of the American Indians' burden and its likely genetic origins.

It was not known until recently whether the endemic of cholesterol gallstones among certain southwestern American Indian tribes was unique among this ethnic group. With use of ultrasonography of the gallbladder and standard diagnostic criteria, gallstones are now found in epidemic proportions in 13 diverse American Indian tribes and communities living in Arizona, Oklahoma, and the Dakotas. We speculate that this predisposition is polygenic involving "thrifty" genes that conferred survival advantages when Paleo-Indians migrated from present-day Siberia to the Americas during the last Great Ice Age approximately 50,000 to 10,000 years ago. A reasonable hypothesis is that functioning of these genes promoted more efficient calorie utilization and storage in the form of adipose tissue. Beneficial results would have been operative during the isolation of Paleo-Indians in the Bering Strait land bridge (Beringia) when thrifty genes would have ensured sufficient fat reserves for survival of prolonged winters, successful pregnancy outcomes, and extended lactation periods. The authors' conjoint work on genetics of experimental cholesterol cholelithiasis in inbred mice promises help in pinpointing orthologous genetic loci (LITH genes) in the human genome. Moreover, the shared environments and homogeneity of American Indian tribes and communities should facilitate discovery of the ensembles of their common and rarer cholesterol gallstone genes. It is anticipated that knowledge of expression, polymorphisms, and functionality of LITH genes will help resolve the molecular mechanisms of this complex heterogeneous trait and thereby provide targets for novel therapies to prevent cholesterol cholelithiasis worldwide.

Cholelithiasis↗
PubMed2003

Genetics of endometriosis: a review of the positional cloning approaches.

There is increasing evidence that endometriosis is inherited as a complex genetic trait in which multiple genes conferring disease susceptibility interact with each other and the environment to produce the phenotype. Research groups worldwide are trying to identify such susceptibility genes through a "positional cloning" approach. This involves mapping their approximate chromosomal localization using linkage analysis by studying the segregation of DNA markers with disease in families without any knowledge of disease mechanisms. The next stage involves choosing a candidate gene in that region, based upon some theoretical or actual knowledge of disease mechanisms, and showing that polymorphisms in that gene occur more frequently in affected individuals than in controls. The approach should produce a clearer understanding of the molecular and cellular mechanisms involved in disease etiology and pathogenesis. It is unlikely that endometriosis is a single disease entity, and it should be possible to categorize the disease into subtypes on the basis of genetic information. The strategy should lead to the discovery of new drug targets, which will be a major advance given that treatment to date has focused upon crude manipulation of ovarian function.

Chromosome Mapping↗
PubMed2000

Genetics of peanut allergy: a twin study.

BACKGROUND: The role of genetics in the etiology of peanut allergy is unknown. For complex genetic traits, twin studies can provide information on the relative contribution of genetic factors to a disease, as the relative confounding effects of environmental factors are markedly decreased. OBJECTIVE: This study was performed to search for evidence that genetic factors influence peanut allergy by comparing the concordance rate for this allergy among monozygotic and dizygotic twins. METHODS: Twin pairs with at least one member with peanut allergy were ascertained through the Food Allergy Network by advertisements in the organization's newsletters and Web site. Individuals with peanut allergy or parental surrogates were interviewed by telephone. A full atopic history was obtained, and peanut allergy and zygosity were determined using previously validated questionnaires. Heritability of peanut allergy was determined using univariate genetic model fitting by maximum likelihood with the Mx statistical modeling software package. RESULTS: Seventy-five twin pairs were recruited. Seventeen pairs were excluded because of unconvincing peanut allergy histories (9 pairs, including 4 of uncertain zygosity) or because one twin had reportedly never ingested peanut (8 pairs). The median age of the 58 remaining twin pairs was 5 years (range 1 to 58 years). Seventy individuals had peanut allergy. In addition to convincing histories of peanut allergy, 52 (74%) had been tested (skin prick testing with or without radioallergosorbent assay) and all had positive reactions to peanut. Twenty-nine of the 70 had experienced >1 reaction to peanut; 29 of 70 had multisystem reactions. Among the monozygotic pairs (n = 14), 9 were concordant for peanut allergy (pairwise concordance, 64.3%) and among dizygotic pairs (n = 44), 3 were concordant for peanut allergy (pairwise concordance, 6.8%; chi(2) = 21.38, P <.0001). Heritability of peanut allergy was estimated at 81. 6% (95% confidence interval 41.6% to 99.7%) with model fitting using a population prevalence of peanut allergy of 0.4%. CONCLUSIONS: The significantly higher concordance rate of peanut allergy among monozygotic twins suggests strongly that there is a significant genetic influence on peanut allergy.

Adolescent↗
PubMed2005

Segmental trisomy of chromosome 17: a mouse model of human aneuploidy syndromes.

Triplication of whole autosomes or large autosomal segments is detrimental to the development of a mammalian embryo. The trisomy of human chromosome (Chr) 21, known as Down's syndrome, is regularly associated with mental retardation and a variable set of other developmental anomalies. Several mouse models of Down's syndrome, triplicating 33-104 genes of Chr16, were designed in an attempt to analyze the contribution of specific orthologous genes to particular developmental features. However, a recent study challenged the concept of dosage-sensitive genes as a primary cause of an abnormal phenotype. To distinguish between the specific effects of dosage-sensitive genes and nonspecific effects of a large number of arbitrary genes, we revisited the mouse Ts43H/Ph segmental trisomy. It encompasses >310 known genes triplicated within the proximal 30 megabases (Mb) of Chr17. We refined the distal border of the trisomic segment to the interval bounded by bacterial artificial chromosomes RP23-277B13 (location 29.0 Mb) and Cbs gene (location 30.2 Mb). The Ts43H mice, viable on a mixed genetic background, exhibited spatial learning deficits analogous to those observed in Ts65Dn mice with unrelated trisomy. Quantitative analysis of the brain expression of 20 genes inside the trisomic interval and 12 genes lying outside on Chr17 revealed 1.2-fold average increase of mRNA steady-state levels of triplicated genes and 0.9-fold average down-regulation of genes beyond the border of trisomy. We propose that systemic comparisons of unrelated segmental trisomies, such as Ts65Dn and Ts43H, will elucidate the pathways leading from the triplicated sequences to the complex developmental traits.

Aneuploidy↗
PubMed2001

Naturally variant autosomal and sex-linked loci determine the severity of iron overload in beta 2-microglobulin-deficient mice.

Hereditary hemochromatosis (HH) is a common chronic human genetic disorder whose hallmark is systemic iron overload. Homozygosity for a mutation in the MHC class I heavy chain paralogue gene HFE has been found to be a primary cause of HH. However, many individuals homozygous for the defective allele of HFE do not develop iron overload, raising the possibility that genetic variation in modifier loci contributes to the HH phenotype. Mice deficient in the product of the beta(2)-microglobulin (beta(2)M) class I light chain fail to express HFE and other MHC class I family proteins, and they have been found to manifest many characteristics of the HH phenotype. To determine whether natural genetic variation plays a role in controlling iron overload, we performed classical genetic analysis of the iron-loading phenotype in beta(2)M-deficient mice in the context of different genetic backgrounds. Strain background was found to be a major determinant in iron loading. Sex played a role that was less than that of strain background but still significant. Resistance and susceptibility to iron overload segregated as complex genetic traits in F(1) and back-cross progeny. These results suggest the existence of naturally variant autosomal and Y chromosome-linked modifier loci that, in the context of mice genetically predisposed by virtue of a beta(2)M deficiency, can profoundly influence the severity of iron loading. These results thus provide a genetic explanation for some of the variability of the HH phenotype.

Aging↗
PubMed2002

An approach for global scanning of single nucleotide variations.

Efficient global scanning of single nucleotide variations in DNA sequences between related, complex DNA samples remains a challenge. In the present article we present an approach to this problem. We have used immobilized thymidine DNA glycosylases to capture and enrich DNA fragments containing internal mismatched base pairs and separate these fragments as a pool from perfectly base-paired fragments as another pool. Enrichments of up to several hundredfold were obtained with one cycle of treatment, and all of the four groups of single nucleotide mismatches were fully covered by combining use of two thymine DNA glycosylases generated here. We have used a heterohybrid-orientating strategy for selective amplification of duplexes with one strand derived from each of two input DNA samples, which can also be used for selective amplification of duplexes with both strands derived from one of two input samples when desired. By combining these methods, the single nucleotide variations either between two DNA pools or within one DNA pool can be obtained in one process. This approach has been applied to the total cDNA from a human cell line and has several potential applications in mapping genetic variations, particularly global scanning of cDNA single nucleotide variations or polymorphisms, and finally high-throughput mapping of complex genetic traits.

Base Pair Mismatch↗
PubMed2000

Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis.

Over 2 billion people are estimated to be infected with virulent Mycobacterium tuberculosis, yet fewer than 10% progress to clinical tuberculosis within their lifetime. Twin studies and variations in the outcome of tuberculosis infection after exposure to similar environmental risks suggest genetic heterogeneity among individuals in their susceptibility to disease. In a mouse model of tuberculosis, we have established that resistance and susceptibility to virulent M. tuberculosis is a complex genetic trait. A new locus with a major effect on tuberculosis susceptibility, designated sst1 (susceptibility to tuberculosis 1), was mapped to a 9-centimorgan (cM) interval on mouse chromosome 1. It is located 10-19 cM distal to a previously identified gene, Nramp1, that controls the innate resistance of mice to the attenuated bacillus Calmette-Guérin vaccine strain. The phenotypic expression of the newly identified locus is distinct from that of Nramp1 in that sst1 controls progression of tuberculosis infection in a lung-specific manner. Mice segregating at the sst1 locus exhibit marked differences in the growth rates of virulent tubercle bacilli in the lungs. Lung lesions in congenic sst1-susceptible mice are characterized by extensive necrosis and unrestricted extracellular multiplication of virulent mycobacteria, whereas sst1-resistant mice develop interstitial granulomas and effectively control multiplication of the bacilli. The resistant allele of sst1, although powerful in controlling infection, is not sufficient to confer full protection against virulent M. tuberculosis, indicating that other genes located outside of the sst1 locus are likely also to be important for controlling tuberculosis infection.

Animals↗
PubMed2002

A general population genetic theory for the evolution of developmental interactions.

The development of most phenotypic traits involves complex interactions between many underlying factors, both genetic and environmental. To study the evolution of such processes, a set of mathematical relationships is derived that describe how selection acts to change the distribution of genetic variation given arbitrarily complex developmental interactions and any distribution of genetic and environmental variation. The result is illustrated by using it to derive models for the evolution of dominance and for the evolutionary consequences of asymmetry in the distribution of genetic variation.

Evolution, Molecular↗
PubMed2003

Frap, FKBP12 rapamycin-associated protein, is a candidate gene for the plasmacytoma resistance locus Pctr2 and can act as a tumor suppressor gene.

Susceptibility to mouse plasmacytomagenesis is a complex genetic trait controlled by several Pctr loci (Pctr1, Pctr2, etc). Congenic strain analysis narrowed the genetic interval surrounding the Pctr2 locus, and genes identified in the interval were sequenced from susceptible BALB/c and resistant DBA/2 mice. Frap (FKBP12 rapamycin-associated protein, mTOR, RAFT) was the only gene differing in amino acid sequence between alleles that correlated with strain sensitivity to tumor development. The in vitro kinase activity of the BALB/c FRAP allele was lower than the DBA/2 allele; phosphorylation of p53 and PHAS1/4EBP1 (properties of heat and acid stability/eukaryotic initiation factor 4E-binding protein) and autophosphorylation of FRAP were less efficient with the BALB/c allele. FRAP also suppressed transformation of NIH 3T3 cells by ras, with DBA/2 FRAP being more efficient than BALB/c FRAP. Rapamycin, a specific inhibitor of FRAP, did not inhibit growth of plasmacytoma cell lines. These studies identify Frap as a candidate tumor suppressor gene, in contrast to many reports that have focused on its prooncogenic properties. Frap may be similar to Tgfb and E2f in exerting both positive and negative growth-regulatory signals, depending on the timing, pathway, or tumor system involved. The failure of rapamycin to inhibit plasma cell tumor growth suggests that FRAP antagonists may not be appropriate for the treatment of plasma cell tumors. Pctr2 joins Pctr1 in possessing alleles that modify susceptibility to plasmacytomagenesis by encoding differences in efficiency of function (efficiency alleles), rather than all-or-none, gain-of-function, or loss-of-function alleles. By analogy, human cancer may also result from the combined effects of several inefficient alleles.

Alleles↗
PubMed2025

Factors underlying a latitudinal gradient in the S/G lignin monomer ratio in natural poplar variants.

The chemical composition of wood plays a pivotal role in the adaptability and structural integrity of trees. However, few studies have investigated the environmental factors that determine lignin composition and its biological significance in plants. Here, we examined the lignin syringyl-to-guaiacyl (S/G) ratio in members of a Populus trichocarpa population sourced from their native habitat and conducted a genome wide association study to identify genes linked to lignin formation. Our results revealed many significant associations, suggesting that lignin biosynthesis is a complex polygenic trait. Additionally, we found an increase in the S/G ratio from northern to southern geographic origin of the trees sampled, along with a corresponding metabolic and transcriptional reprogramming of xylem cell wall biosynthesis. Further molecular analysis identified a mutation in a cell wall laccase genetically associated with higher S/G ratios that predominate in trees from warmer lower latitudes. Collectively, our findings suggest that lignin heterogeneity arises from an evolutionary process enabling poplar adaptation to different climatic challenges.

Populus↗
PubMed1993

Genetic mapping of tumor susceptibility genes involved in mouse plasmacytomagenesis.

Plasmacytomas (PCTs) were induced in 47% of BALB/cAnPt mice by the intraperitoneal injection of pristane, in 2% of (BALB/c x DBA/2N)F1, and in 11% of 773 BALB/cAnPt x (BALB/cAnPt x DBA/2N)F1 N2 backcross mice. This result indicates a multigenic mode of inheritance for PCT susceptibility. To locate genes controlling this complex genetic trait, tumor susceptibility in backcross progeny generated from BALB/c and DBA/2N (resistant) mice was correlated with alleles of 83 marker loci. The genotypes of the PCT-susceptible progeny displayed an excess homozygosity for BALB/c alleles within a 32-centimorgan stretch of mouse chromosome 4 (> 95% probability of linkage) with minimal recombination (12%) near Gt10. Another susceptibility gene on mouse chromosome 1 may be linked to Fcgr2 (90% probability of linkage); there were excess heterozygotes for Fcgr2 among the susceptible progeny and excess homozygotes among the resistant progeny. Regions of mouse chromosomes 4 and 1 that are correlated with PCT susceptibility share extensive linkage homology with regions of human chromosome 1 that have been associated with cytogenetic abnormalities in multiple myeloma and lymphoid, breast, and endocrine tumors.

Animals↗
PubMed2003

The future of psychiatric genetics.

Geneticists have been predicting that advances in their discipline will revolutionize the understanding of human disease and behavior. While there has been considerable progress in disorders showing simple, Mendelian patterns of inheritance, expectations have yet to be fulfilled for disorders and traits showing complex inheritance. In this article, we consider the difficulties that complex diseases pose to genetic research, discuss progress and make suggestions regarding future directions.

Animals↗
PubMed2004

Genomics and the Human Genome Project: implications for psychiatry.

In the past decade the Human Genome Project has made extraordinary strides in understanding of fundamental human genetics. The complete human genetic sequence has been determined, and the chromosomal location of almost all human genes identified. Presently, a large international consortium, the HapMap Project, is working to identify a large portion of genetic variation in different human populations and the structure and relationship of these variants to each other. The Human Genome Project has approached human genetics on a scale not previously seen in biology. This has been made possible by dramatic advances in high throughput technology and bio-informatics. Tools such as gene chips and micro-arrays have spawned an entirely new strategy to examine the function and expression of genes in a massively parallel fashion. Together these tools have dramatically advanced our knowledge about the human genome. They promise powerful new approaches to complex genetic traits such as psychiatric illness. The goals and progress of the Human Genome Project and the technology involved are reviewed. The implications of this science for psychiatric genetics are discussed.

Computational Biology↗