Biomedical subjects

Jeffrey R Gulcher

Publications and source records attributed to Jeffrey R Gulcher.

At least 19 recordsLinked to original sources

PubMed2004

Familial risk of lung carcinoma in the Icelandic population.

CONTEXT: The dominant role of tobacco smoke as a causative factor in lung carcinoma is well established; however, an inherited predisposition may also be an important factor in the susceptibility to lung carcinoma. OBJECTIVE: To investigate the contribution of genetic factors to the risk of developing lung carcinoma in the Icelandic population. DESIGN, SETTING, AND PARTICIPANTS: Risk ratios (RRs) of lung carcinoma for first-, second-, and third-degree relatives of patients with lung carcinoma were estimated by linking records from the Icelandic Cancer Registry (ICR) of all 2756 patients diagnosed with lung carcinoma within the Icelandic population from January 1, 1955, to February 28, 2002, with an extensive genealogical database containing all living Icelanders and most of their ancestors since the settlement of Iceland. The RR for smoking was similarly estimated using a random population-based cohort of 10,541 smokers from the Reykjavik Heart Study who had smoked for more than 10 years. Of these smokers, 562 developed lung cancer based on the patients with lung cancer list from the ICR. MAIN OUTCOME MEASURES: Estimation of RRs of close and distant relatives of patients with lung carcinoma and comparison with RRs for close and distant relatives of smokers. RESULTS: A familial factor for lung carcinoma was shown to extend beyond the nuclear family, as evidenced by significantly increased RR for first-degree relatives (for parents: RR, 2.69; 95% confidence interval [CI], 2.20-3.23; for siblings: RR, 2.02; 95% CI, 1.77-2.23; and for children: RR, 1.96; 95% CI, 1.53-2.39), second-degree relatives (for uncles/aunts: RR, 1.34; 95% CI, 1.15-1.49; and for nephews/nieces: RR, 1.28; 95% CI, 1.10-1.43), and third-degree relatives (for cousins: RR, 1.14; 95% CI, 1.05-1.22) of patients with lung carcinoma. This effect was stronger for relatives of patients with early-onset disease (age at onset < or =60 years) (for parents: RR, 3.48; 95% CI, 1.83-8.21; for siblings: RR, 3.30; 95% CI, 2.19-4.58; and for children: RR, 2.84; 95% CI, 1.34-7.21). The hypothesis that this increased risk is solely due to the effects of smoking was rejected for all relationships, except cousins and spouses, with a single-sided test of the RRs for lung carcinoma vs RRs for smoking. CONCLUSIONS: These results underscore the importance of genetic predisposition in the development of lung carcinoma, with its strongest effect in patients with early-onset disease. However, tobacco smoke plays a dominant role in the pathogenesis of this disease, even among those individuals who are genetically predisposed to lung carcinoma.

Adenocarcinoma↗

PubMed2004

Multiple novel transcription initiation sites for NRG1.

The large neuregulin 1 gene (NRG1) has been mapped to a 1.125 Mb region on chromosome 8p11-21. Three major forms of NRG1 (types I-III), all with distinct amino-termini encoded by unique 5'-exons, have been described. We report here the discovery of nine novel NRG1 exons, including six alternative 5'-exons, increasing the number of potential promoters in NRG1 from three to nine. The novel transcripts of NRG1 described here use the novel 5'-exons which are either coding or non-coding. The functional relevance of the predicted proteins they encode has not been evaluated. Three of the novel 5'-exons are well conserved in syntenic rat and mouse sequences; they encode proteins with novel amino-termini, here termed types IV-VI. NRG1 plays a central role in neural development and is most likely involved in regulation of synaptic plasticity, or how the brain responds or adapts to the environment. The unusually complex gene structure may facilitate spatial and temporal regulation of NRG1 expression, fine-tune NRG1 protein function at different stages during development of the nervous system, and adapt responses to the environment in the adult brain.

5' Flanking Region↗

PubMed2004

Recombination rate and reproductive success in humans.

Intergenerational mixing of DNA through meiotic recombinations of homologous chromosomes during gametogenesis is a major event that generates diversity in the eukaryotic genome. We examined genome-wide microsatellite data for 23,066 individuals, providing information on recombination events of 14,140 maternal and paternal meioses each, and found a positive correlation between maternal recombination counts of an offspring and maternal age. We postulated that the recombination rate of eggs does not increase with maternal age, but that the apparent increase is the consequence of selection. Specifically, a high recombination count increased the chance of a gamete becoming a live birth, and this effect became more pronounced with advancing maternal age. Further support for this hypothesis came from our observation that mothers with high oocyte recombination rate tend to have more children. Hence, not only do recombinations have a role in evolution by yielding diverse combinations of gene variants for natural selection, but they are also under selection themselves.

Adolescent↗

PubMed2004

A novel TEAD1 mutation is the causative allele in Sveinsson's chorioretinal atrophy (helicoid peripapillary chorioretinal degeneration).

Sveinsson's chorioretinal atrophy (SCRA), also referred to as helicoid peripapillary chorioretinal degeneration or atrophia areata, is an autosomal dominant eye disease, characterized by symmetrical lesions radiating from the optic disc involving the retina and the choroid. Genome-wide linkage analysis mapped the SCRA gene to chromosome 11p15 in 81 patients from a large founder pedigree in Iceland. The parametric LOD score obtained was 18.9 using an autosomal dominant model with high penetrance. Crossover analysis of the linkage region with 51 markers identified a 593 kb segment shared by all patients. Sequencing exons of the only gene in this interval, the transcriptional enhancer TEAD1, revealed a novel missense mutation (Y421H) carried by all patients and none of the 502 controls. The mutation is in a conserved amino acid sequence in the C terminal of the protein, a potential binding site for YAP65 one of TEAD1's cofactors that is expressed in human retina as well as TEAD1 based on RT-PCR experiments. Therefore, we conclude that the mutation in the TEAD1 gene is the cause of Sveinsson's chorioretinal atrophy.

Adaptor Proteins, Signal Transducing↗

PubMed2004

The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke.

We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13. A four-marker single-nucleotide polymorphism (SNP) haplotype in this locus spanning the gene ALOX5AP encoding 5-lipoxygenase activating protein (FLAP) is associated with a two times greater risk of myocardial infarction in Iceland. This haplotype also confers almost two times greater risk of stroke. Another ALOX5AP haplotype is associated with myocardial infarction in individuals from the UK. Stimulated neutrophils from individuals with myocardial infarction produce more leukotriene B4, a key product in the 5-lipoxygenase pathway, than do neutrophils from controls, and this difference is largely attributed to cells from males who carry the at-risk haplotype. We conclude that variants of ALOX5AP are involved in the pathogenesis of both myocardial infarction and stroke by increasing leukotriene production and inflammation in the arterial wall.

5-Lipoxygenase-Activating Proteins↗

PubMed2004

Neuregulin 1 and schizophrenia.

We discuss in this review the role of the neuregulin (NRG1) gene in schizophrenia. NRG1 contributes to the genetics of schizophrenia in both Icelandic and Scottish schizophrenia patients. NRG1 participates in glutamatergic signaling by regulating the N-methyl-D-aspartate (NMDA) receptor through the interaction of the NRG1 protein and its receptors. NRG1 plays a central role in neural development and is most likely involved in regulating synaptic plasticity, or how the brain responds or adapts to the environment. The discovery that defects in NRG1 signaling may be involved in some cases of schizophrenia, not only implicates NRG1, but suggests that its biological pathway, active both at developing and mature synapses, is worth inspecting further in a search for other schizophrenia genes possibly in epistasis with NRG1.

Animals↗

PubMed2004

Association of vitamin D binding protein variants with chronic mucus hypersecretion in Iceland.

BACKGROUND: Previous studies of vitamin D binding protein (VDBP, also known as group-specific component, Gc, encoded by the GC gene) have implicated two gene variants, GC*2 and GC*1F, as possible contributors with chronic obstructive pulmonary disease (COPD) protection and susceptibility, respectively. The objective of this study was to examine the association of VDBP to different subtypes of COPD. STUDY DESIGN: The association of the various GC genotypes to the COPD phenotype was examined in Icelandic COPD patients who were followed by pulmonary physicians at the University Hospital of Iceland. METHODS: All patients were genotyped for the known alleles of the GC gene. The single nucleotide polymorphisms (SNPs) were identified by a restriction fragment length polymorphism procedure. Study power was estimated based on allele frequencies of the variants, and risk ratios were calculated from the prevalence of genotypes in the affected group divided by its prevalence in the control population. Statistical analyses were performed using the 2-tailed Fisher's Exact Test and chi(2) test, where appropriate. PATIENT GROUP: One hundred and two COPD patients and 183 controls, together with 46 asthma patients and 48 patients with chronic mucous hypersecretion (CMH) were examined. MAIN OUTCOME MEASURE AND RESULTS: The results demonstrate similar allele and genotype frequencies of GC in COPD patients overall and healthy controls. However, there was a higher prevalence of genotypes carrying a GC*1F allele and lower prevalence of genotypes with a GC*2 allele in the CMH patients than in controls. This difference was most notable in the homozygous form: 8.3% vs 1.1% for the GC*1F/*1F, and 0.0% vs 7.6% for the GC*2/*2 genotypes, respectively. When controlled for smoking, only the non-smoking CMH patients demonstrated a significantly altered frequency of the GC*1F/*1F genotype (p = 0.0001). The prevalence of the GC*2/*2 genotype was also significantly lower in patients with bronchial hypersecretion with airflow obstruction compared with the control group (2.9% vs 7.6%). Taken together, these results demonstrate that the GC*1F and GC*2 alleles are associated with sputum hypersecretion in individuals who are at increased risk of developing COPD.

Asthma↗

PubMed2003

Linkage of osteoporosis to chromosome 20p12 and association to BMP2.

Osteoporotic fractures are a major cause of morbidity and mortality in ageing populations. Osteoporosis, defined as low bone mineral density (BMD) and associated fractures, have significant genetic components that are largely unknown. Linkage analysis in a large number of extended osteoporosis families in Iceland, using a phenotype that combines osteoporotic fractures and BMD measurements, showed linkage to Chromosome 20p12.3 (multipoint allele-sharing LOD, 5.10; p value, 6.3 x 10(-7)), results that are statistically significant after adjusting for the number of phenotypes tested and the genome-wide search. A follow-up association analysis using closely spaced polymorphic markers was performed. Three variants in the bone morphogenetic protein 2 (BMP2) gene, a missense polymorphism and two anonymous single nucleotide polymorphism haplotypes, were determined to be associated with osteoporosis in the Icelandic patients. The association is seen with many definitions of an osteoporotic phenotype, including osteoporotic fractures as well as low BMD, both before and after menopause. A replication study with a Danish cohort of postmenopausal women was conducted to confirm the contribution of the three identified variants. In conclusion, we find that a region on the short arm of Chromosome 20 contains a gene or genes that appear to be a major risk factor for osteoporosis and osteoporotic fractures, and our evidence supports the view that BMP2 is at least one of these genes.

Alleles↗

PubMed2003

Localization of a gene for migraine without aura to chromosome 4q21.

Migraine is a common form of headache and has a significant genetic component. Here, we report linkage results from a study in Iceland of migraine without aura (MO). The study group comprised patients with migraine recruited by neurologists and from the registry of the Icelandic Migraine Society, as well as through the use of a questionnaire sent to a random sample of 20,000 Icelanders. Migraine diagnoses were made and confirmed using diagnostic criteria established by the International Headache Society. A genome-wide scan with multipoint allele-sharing methods was performed on 289 patients suffering from MO. Linkage was observed to a locus on chromosome 4q21 (LOD=2.05; P=.001). The locus reported here overlaps a locus (MGR1) reported elsewhere for patients with migraine with aura (MA) in the Finnish population. This replication of the MGR1 locus in families with MO indicates that the gene we have mapped may contribute to both MA and MO. Further analysis indicates that the linkage evidence improves for affected females and, especially, with a slightly relaxed definition of MO (LOD=4.08; P=7.2 x 10(-6)).

Alleles↗

PubMed2003

The gene encoding phosphodiesterase 4D confers risk of ischemic stroke.

We previously mapped susceptibility to stroke to chromosome 5q12. Here we finely mapped this locus and tested it for association with stroke. We found the strongest association in the gene encoding phosphodiesterase 4D (PDE4D), especially for carotid and cardiogenic stroke, the forms of stroke related to atherosclerosis. Notably, we found that haplotypes can be classified into three distinct groups: wild-type, at-risk and protective. We also observed a substantial disregulation of multiple PDE4D isoforms in affected individuals. We propose that PDE4D is involved in the pathogenesis of stroke, possibly through atherosclerosis, which is the primary pathological process underlying ischemic stroke.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2003

Localization of a susceptibility gene for type 2 diabetes to chromosome 5q34-q35.2.

We report a genomewide linkage study of type 2 diabetes (T2D [MIM 125853]) in the Icelandic population. A list of type 2 diabetics was cross-matched with a computerized genealogical database clustering 763 type 2 diabetics into 227 families. The diabetic patients and their relatives were genotyped with 906 microsatellite markers. A nonparametric multipoint linkage analysis yielded linkage to 5q34-q35.2 (LOD = 2.90, P=1.29 x 10(-4)) in all diabetics. Since obesity, here defined as body mass index (BMI) > or =30 kg/m(2), is a key risk factor for the development of T2D, we studied the data either independently of BMI or by stratifying the patient group as obese (BMI > or =30) or nonobese (BMI <30). A nonparametric multipoint linkage analysis yielded linkage to 5q34-q35.2 (LOD = 3.64, P=2.12 x (10)-5) in the nonobese diabetics. No linkage was observed in this region for the obese diabetics. Linkage analysis conditioning on maternal transmission to the nonobese diabetics resulted in a LOD score of 3.48 (P=3.12 x 10(-5)) in the same region, whereas conditioning on paternal transmission led to a substantial drop in the LOD score. Finally, we observed potential interactions between the 5q locus and two T2D susceptibility loci, previously mapped in other populations.

Aged↗

PubMed2003

Genomewide scan for hand osteoarthritis: a novel mutation in matrilin-3.

Osteoarthritis (OA) is the most common human joint disease, characterized by loss and/or remodeling of joint synovium, cartilage, and bone. Here, we describe a genomewide linkage analysis of patients with idiopathic hand OA who were carefully phenotyped for involvement of either or both the distal interphalangeal (DIP) joints and the first carpometacarpal (CMC1) joints. The best linkage peaks were on chromosomes 4q and 3p and on the short arm of chromosome 2. Genomewide significance was reached for a locus on chromosome 2 for patients with affected CMC1 joints (LOD = 4.97); this locus was also significant for patients with OA in both CMC1 and DIP joints (LOD = 4.44). The peak LOD score at this locus coincides with a gene, MATN3, encoding the noncollagenous cartilage extracellular matrix protein, matrilin-3. Subsequent screening of the genomic sequence revealed a missense mutation, of a conserved amino acid codon, changing threonine to methionine in the epidermal growth factor-like domain in matrilin-3. The missense mutation cosegregates with hand OA in several families. The mutation frequency is slightly more than 2% in patients with hand OA in the Icelandic population and has a relative risk of 2.1.

Amino Acid Sequence↗

PubMed2003

A populationwide coalescent analysis of Icelandic matrilineal and patrilineal genealogies: evidence for a faster evolutionary rate of mtDNA lineages than Y chromosomes.

Historical inferences from genetic data increasingly depend on assumptions about the genealogical process that shapes the frequencies of alleles over time. Yet little is known about the structure of human genealogies over long periods of time and how they depart from expectations of standard demographic models, such as that attributed to Wright and Fisher. To obtain such information and to examine the recent evolutionary history of mtDNA and Y-chromosome haplotypes in the Icelandic gene pool, we traced the matrilineal and patrilineal ancestry of all 131,060 Icelanders born after 1972 back to two cohorts of ancestors, one born between 1848 and 1892 and the other between 1798 and 1742. This populationwide coalescent analysis of Icelandic genealogies revealed highly positively skewed distributions of descendants to ancestors, with the vast majority of potential ancestors contributing one or no descendants and a minority of ancestors contributing large numbers of descendants. The expansion and loss of matrilines and patrilines has caused considerable fluctuation in the frequencies of mtDNA and Y-chromosome haplotypes, despite a rapid population expansion in Iceland during the past 300 years. Contrary to a widespread assumption, the rate of evolution caused by this lineage-sorting process was markedly faster in matrilines (mtDNA) than in patrilines (Y chromosomes). The primary cause is a 10% shorter matrilineal generation interval. Variance in the number of offspring produced within each generation was not an important differentiating factor. We observed an intergenerational correlation in offspring number and in the length of generation intervals in the matrilineal and patrilineal genealogies, which was stronger in matrilines and thus contributes to their faster evolutionary rate. These findings may have implications for coalescent date estimates based on mtDNA and Y chromosomes.

Alleles↗

PubMed2003

Anxiety with panic disorder linked to chromosome 9q in Iceland.

The results of a genomewide scan for genes conferring susceptibility to anxiety disorders in the Icelandic population are described. The aim of the study was to locate genes that predispose to anxiety by utilizing the extensive genealogical records and the relative homogeneity of the Icelandic population. Participants were recruited in two stages: (1) Initial case-identification by a population screening for anxiety disorders, using the Stamm Screening Questionnaire, was followed by aggregation into extended families, with the help of our genealogy database; and (2) those who fulfilled the diagnostic and family aggregation criteria underwent a more detailed diagnostic workup based on the Composite International Diagnostic Interview. Screening for anxiety in close relatives also identified additional affected members within the families. After genotyping was performed with 976 microsatellite markers, affected-only linkage analysis was done, and allele-sharing LOD scores were calculated using the program Allegro. Linkage analysis of 25 extended families, in each of which at least one affected individual had panic disorder (PD), resulted in a LOD score of 4.18 at D9S271, on chromosome 9q31. The intermarker distance was 4.4 cM on average, whereas it was 1.5 cM in the linked region as additional markers were added to increase the information content. The linkage results may be relevant not only to PD but also to anxiety in general, since our linkage study included patients with other forms of anxiety.

Anxiety↗

PubMed2003

deCODE genetics, Inc.

deCODE genetics, Inc. has compiled the world's most comprehensive collection of population data on genealogy, genotypes and phenotypes. This combination of resources provides an effective system for identifying key genes linked to common diseases and to the regulation of drug response. deCODE has successfully mapped genes in over 25 common complex diseases and isolated genes in eight of these. The methodology used to map these genes is based upon the company's genealogical database of the Icelandic population, which enables deCODE scientists to efficiently conduct population- and genome-wide linkage studies to identify key genetic factors involved in phenotypes ranging from diseases to drug response. In its growing pharmacogenomics program, deCODE has combined this linkage approach with high-throughput expression profiling to develop accurate tests that can predict individual responsiveness to virtually any drug of interest. deCODE is applying its unrivaled discovery capabilities to bring to market new drugs, DNA-based diagnostic products and pharmacogenomic tests. The company believes that such tests will play a crucial role in delivering personalized medicine - contributing to the development of more effective means of diagnosing and treating disease by matching each patient with the most suitable drug.

Chromosome Mapping↗

PubMed2002

Association of neuregulin 1 with schizophrenia confirmed in a Scottish population.

Recently, we identified neuregulin 1 (NRG1) as a susceptibility gene for schizophrenia in the Icelandic population, by a combined linkage and association approach. Here, we report the first study evaluating the relevance of NRG1 to schizophrenia in a population outside Iceland. Markers representing a core at-risk haplotype found in Icelanders at the 5' end of the NRG1 gene were genotyped in 609 unrelated Scottish patients and 618 unrelated Scottish control individuals. This haplotype consisted of five SNP markers and two microsatellites, which all appear to be in strong linkage disequilibrium. For the Scottish patients and control subjects, haplotype frequencies were estimated by maximum likelihood, using the expectation-maximization algorithm. The frequency of the seven-marker haplotype among the Scottish patients was significantly greater than that among the control subjects (10.2% vs. 5.9%, P=.00031). The estimated risk ratio was 1.8, which is in keeping with our report of unrelated Icelandic patients (2.1). Three of the seven markers in the haplotype gave single-point P values ranging from .000064 to .0021 for the allele contributing to the at-risk haplotype. This direct replication of haplotype association in a second population further implicates NRG1 as a factor that contributes to the etiology of schizophrenia.

Algorithms↗

PubMed2002

A susceptibility gene for psoriatic arthritis maps to chromosome 16q: evidence for imprinting.

Several genetic loci have been reported for psoriasis, but none has been specifically linked to psoriatic arthritis (PsA), a condition that affects >10% of patients with psoriasis. A genetic component for PsA is suggested by segregation within families and high concordance among identical twins. We performed a linkage scan to map genes contributing to PsA. We identified 178 patients with PsA out of 906 patients who were included in our genetic study of psoriasis. Using a comprehensive genealogy database, we were able to connect 100 of these into 39 families. We genotyped the patients using a framework marker set of 1,000 microsatellite markers, with an average density of 3 cM, and performed multipoint, affected-only, allele-sharing linkage analysis using the Allegro program. On the basis of the initial results, we genotyped more markers for the most prominent loci. A linkage with a LOD score of 2.17 was observed on chromosome 16q. The linkage analysis, conditioned on paternal transmission to affected individuals, gave a LOD score of 4.19, whereas a LOD score of only 1.03 was observed when conditioned for maternal transmission. A suggestive locus on chromosome 16q has previously been implicated in psoriasis. Our data indicate that a gene at this locus may be involved in paternal transmission of PsA.

Alleles↗

PubMed2002

Neuregulin 1 and susceptibility to schizophrenia.

The cause of schizophrenia is unknown, but it has a significant genetic component. Pharmacologic studies, studies of gene expression in man, and studies of mouse mutants suggest involvement of glutamate and dopamine neurotransmitter systems. However, so far, strong association has not been found between schizophrenia and variants of the genes encoding components of these systems. Here, we report the results of a genomewide scan of schizophrenia families in Iceland; these results support previous work, done in five populations, showing that schizophrenia maps to chromosome 8p. Extensive fine-mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia. NRG1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors. Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, NRG1 hypomorphs have fewer functional NMDA receptors than wild-type mice. We also demonstrate that the behavioral phenotypes of the NRG1 hypomorphs are partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia.

Animals↗