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PubMed2026

Genetic architecture of postpartum psychosis: from common to rare genetic variation.

Postpartum psychosis is a severe psychiatric condition marked by the abrupt onset of psychosis, mania, or psychotic depression following childbirth. Despite evidence for a strong genetic basis, the roles of common and rare genetic variation remain poorly understood. Leveraging data from Swedish national registers and genomic data from the All of Us Research Program, we estimated family-based heritability at 55% and whole-genome sequencing-based heritability at 46%. Rare coding variant analysis identified HMGCR as a gene in which rare damaging variants confer risk for postpartum psychosis (FDR&#x2009;<&#x2009;0.05). Analyses of 240,009 participants from the All of Us Research Program and 58,990 participants from the Mount Sinai BioMe Biobank identified significant associations linking deleterious rare variants in HMGCR to vascular dementia and mental disorder, not otherwise specified, supporting the gene's broader psychiatric relevance. Additionally, among the top 200 genes ranked by association statistics, 17% of bipolar disorder, 21% of schizophrenia, and 16-25% of multiple autoimmune disorders exhibit a possible association with postpartum psychosis. These findings reveal unique genetic contributions and shared pathways, providing a foundation for understanding pathophysiology and advancing therapeutic strategies.

Humans↗
PubMed2006

Genetic variation in myosin IXB is associated with ulcerative colitis.

BACKGROUND & AIMS: Common germline genetic variation in the 3' region of myosin IXB (MYO9B) has been associated recently with susceptibility to celiac disease, with a hypothesis that MYO9B variants might influence intestinal permeability. These findings suggested the current study investigating a possible further role for MYO9B variation in inflammatory bowel disease. METHODS: Eight single-nucleotide polymorphisms (SNPs) were selected to tag common haplotypes from the 35-kb 3' region of MYO9B. These included the strongest celiac disease-associated variants reported in a Dutch cohort. These SNPs were studied in 3 independently collected and genotyped case-control cohorts of European descent (UK, Dutch, and Canadian/Italian), comprising in total 2717 inflammatory bowel disease patients (1197 with Crohn's disease, 1520 with ulcerative colitis) and 4440 controls. RESULTS: Common variation in MYO9B was associated with susceptibility to inflammatory bowel disease in all 3 cohorts examined (most associated SNP, rs1545620; meta-analysis P = 1.9 x 10(-6); odds ratio, 1.2), with the same alleles showing association as reported for celiac disease. CONCLUSIONS: MYO9B genetic variants predispose to inflammatory bowel disease. Interestingly, rs1545620 is a nonsynonymous variant leading to an amino acid change (Ala1011Ser) in the third calmodulin binding IQ domain of MYO9B. Unlike previous variants (in other genes) reported to predispose to inflammatory bowel disease, the association at MYO9B was considerably stronger with ulcerative colitis, although weaker association with Crohn's disease also was observed. These data imply shared causal mechanisms underlying intestinal inflammatory diseases.

Adolescent↗
PubMed2006

HapMap-based study of the 17q21 ERBB2 amplicon in susceptibility to breast cancer.

ERBB2 is frequently amplified in breast tumours as part of a wide region of amplification on chromosome 17q21. This amplicon contains many candidate genes for breast cancer susceptibility. We used a genetic association study design to determine if common genetic variation (frequency>or=5%) in a 400-kb region surrounding ERBB2 and containing the PPARBP, CRK7, NEUROD2, PPP1R1B, STARD3, TCAP, PNMT, CAB2, ERBB2, C17ORF37, GRB7 and ZNFN1A3 genes, was associated with breast cancer risk. Sixteen tagging single-nucleotide polymorphisms (tSNPs) selected within blocks of linkage disequilibrium from the HapMap database, one HapMap singleton SNP, and six additional SNPs randomly selected from dbSNP were genotyped using Taqman in a large study set of British women (2275 cases, 2280 controls). We observed no association between any of the genotypes or associated haplotypes and disease risk. In order to simulate unidentified SNPs, we performed the leave-one-out cross-validation procedure on the HapMap data; over 90% of the common genetic variation was well represented by tagging polymorphisms. We are therefore likely to have tagged any common variants present in our population. In summary, we found no association between common genetic variation in the 17q21 ERBB2 amplicon and breast cancer risk in British women.

Adult↗
PubMed1978

Galactose-1-phosphate uridyl transferase deficiency due to Duarte/galactosemia combined variation: clinical and biochemical studies.

The most common abnormality detected by the screening of newborn infants for galactosemia is a deficiency of galactose-1-phosphate uridyl transferase due to the presence in one individual of allelic genes for the Duarte variant and for galactosemia. Clinical studies of ten untreated individuals with this genetic compound, including three adults, failed to reveal evidence of cataracts, liver disease, or mental subnormality, the major clinical complications associated with galactosemia. Galactose-1-phosphate was not detectable in umbilical cord blood from one infant. Galactose was not detectable in random blood specimens from any of the individuals and was present in only small amounts following ingestion of milk in one infant and a child. It would appear that this common gentic variation is usually, if not always, benign.

Adult↗
PubMed2000

Circadian variation in witnessed out of hospital cardiac arrest.

OBJECTIVES: To examine the effect on circadian variation of out of hospital cardiac arrest according to the underlying aetiology and presenting rhythm of arrest, and to explore strategies that might help to improve survival outcome using circadian variation. DESIGN: Population based retrospective study. SETTING: County of Nottinghamshire with a total population of 993 914 and an area of 2183 km(2). SUBJECTS: Between 1 January 1991 and 3 December 1994, all witnessed cardiac arrests attended by the Nottinghamshire Ambulance Service, of which 1196 patients had a cardiac cause for their arrest (ICD, 9th revision, codes 390-414 and 420-429) and 339 had a non-cardiac cause. RESULTS: The circadian variation of the cardiac cases was not significantly different from that of non-cardiac cases (p = 0.587), even when adjusted for age, sex, or presenting rhythm of arrest. For cardiac cases, the circadian variation of those who presented with ventricular fibrillation was significantly different from those presenting with a rhythm other than ventricular fibrillation (p = 0.005), but was similar to the circadian variation of bystander cardiopulmonary resuscitation (p = 0.306) and survivors (p = 0.542). Ambulance response time was also found to have a circadian variation. CONCLUSIONS: There is a common circadian variation of out of hospital cardiac arrest, irrespective of underlying aetiology, where the presenting rhythm is other than ventricular fibrillation. This is different from the circadian variation of cases of cardiac aetiology presenting with ventricular fibrillation. The circadian variation of ventricular fibrillation, and consequently survival, may be affected by the availability of bystander cardiopulmonary resuscitation and the speed of ambulance response.

Aged↗
PubMed2004

Common genetic effects on variation in impulsivity and activity in mice.

Impulsivity is a complex psychological construct that impacts on behavioral predispositions in the normal range and has been shown to have a genetic element through the examination of hereditary patterns of abnormal conditions such as attention deficit/hyperactivity disorder and obsessive compulsive disorder. In this study, we took advantage of the isogenic nature of inbred strains of mice to determine the contribution of genes to impulsive behaviors by examining the performance of four separate mouse strains in a novel murine delayed-reinforcement paradigm, during which the animals had to choose between rewards that were relatively small but available immediately and larger but progressively delayed rewards. To control for maternal effects, all the mice were cross-fostered to a common strain immediately after birth. Under these conditions, we found significant differences between the strains on behaviors indexing impulsive choice and on independent measures of locomotor activity, which subsequent heritability analysis showed could be related, in part, to genetic effects. Moreover, the two aspects of behavior were found to co-vary, with the more active animals also displaying more impulsive behavior. This was not attributable to mundane confounds related to individual task requirements but instead indicated the existence of common genetic factors influencing variation in both impulsivity and locomotor activity. The data are discussed in terms of the coexistence of impulsivity and hyperactivity, interactions between environmental and genetic effects, and possible candidate genes.

Animals↗
PubMed2000

Phenotypic covariance structure in tamarins (genus Saguinus): a comparison of variation patterns using matrix correlation and common principal component analysis.

Constancy of variation/covariation structure among populations is frequently assumed in order to measure the differential selective forces which have caused population differentiation through evolutionary time. Following Steppan ([1997] Evolution 51:571-594), this assumption is examined among closely related tamarin species (genus Saguinus), using two distinct approaches applied to the task of evaluating similarity in patterns of morphological variation: common principal component analysis and matrix correlations. While the results of these analyses may appear contradictory, closer examination reveals them as complementary, highlighting the wisdom of combined methodologies. Overall, the results reveal a close relationship among the morphologically based variance structures of the tamarin species a relationship whose pattern is consistent with the pattern of phylogenetic relatedness as found via a molecular genetic study. More specifically, both methodological approaches provide some support for divergence of S. geoffroyi and S. oedipus (with regards to their patterns of morphological variation) from other tamarin species. This suggests that variance/covariance structure may have diverged through evolutionary time in the tamarin lineage, placing assumptions of constancy in doubt.

Analysis of Variance↗
PubMed2000

A variant of an accessory common bile duct.

While variations of the common bile duct are relatively common, true duplication of the common bile duct is very rare. Such deviation from normal anatomy, if unrecognized, may cause problems during surgical intervention. Here we present a case of a unique variant of an accessory bile duct which arises from the confluence of the right and left hepatic ducts and runs down to join the pancreatic duct to form a long, common channel before opening into the papilla with the main duct.

Adult↗
PubMed2006

Spatial variation of mortality for common and rare cancers in Piedmont, Italy, from 1980 to 2000: a Bayesian approach.

A Bayesian hierarchical model was used to study the spatial variation in mortality risk from lung and pleural cancer in both sexes, and breast and soft tissue sarcoma (STS) in women in Piedmont (north-west Italy, average population 4 349 411) from 1980 to 2000. Of these four neoplasms, two are common (lung and breast) and two rare (pleura and STS); two have well recognized risk factors (lung and pleura) while the other two (breast and STS) have no single strong risk factor. Data were analysed at a small-area level (1206 municipalities, population 39 to 989 663), using both standardized mortality ratios and Bayesian-estimated mortality risks. The Bayesian model allowed for both heterogeneity (through spatially independent random effects) and clustering (through spatially correlated random effects) and, by borrowing information from neighbouring areas, provided stable estimates for areas with sparse data. The aim was to reduce the noise in the disease maps to highlight the true underlying mortality distribution. Lung cancer in men showed strong spatial structure with a marked east-west gradient, but no appreciable urban-rural differences. In contrast, high mortality areas for female lung cancer were observed around conurbations. Female breast cancer and STS appeared to be spread uniformly across the region. Pleural cancer mortality clusters were evident around areas with major asbestos manufacturers, or natural asbestiform fibre pollution. Maps of Bayesian-estimated mortality risk provided appreciably clearer pictures of risk distribution than did maps of the standardized mortality ratio.

Bayes Theorem↗
PubMed2002

[SNP collection, pharmacogenomics, and the future of drug therapy].

Common genetic variations may, in large part, explain genetic predispositions to common diseases and individual differences in pharmacological responsiveness. Single-nucleotide polymorphisms (SNPs) are the most frequent type of genetic variation, and are thought to be present every several-hundred bases, on average, throughout the human genome. SNPs can provide medically important information through (1) their contribution to high-density maps for studies of susceptibility to common diseases; (2) provision of genetic data for personalized medical service; and (3) identification of genes associated with the efficacy and side-effect of drugs. We have been focusing on genomic loci that encode various enzymes and transporters involved in the metabolism of drugs, and have described more than 5,500 SNP and other variations. Our collection of human variations should prove useful for investigations designed to detect associations between genetic variations and common diseases or responsiveness to drug therapy. In this review we introduce the recent progress and future direction of human genome analysis and its impact on medicine.

ATP Binding Cassette Transporter 1↗
PubMed2001

Detection and typing of human papillomavirus in anal epidermoid carcinomas: sequence variation in the E7 gene of human papillomavirus Type 16.

INTRODUCTION: Human papillomavirus, particularly Type 16, plays a central role in the development of anogenital squamous-cell carcinomas. A common sequence variation of human papillomavirus Type 16 in cervical cancer cell lines and in cervical cancer tissues from Korean patients was recently reported. The present study was performed to determine the integration type of human papillomavirus DNA in anal epidermoid carcinoma and to identify the common sequence variations in the human papillomavirus Type 16 E7 gene that had been previously reported. METHODS: Twenty-one formalin-fixed, paraffin-embedded specimens collected from 29 patients with anal epidermoid carcinomas treated at the Seoul National University Hospital over a ten-year period (1989-1998) were investigated. Genomic DNA from the 21 specimens was extracted and analyzed using the polymerase chain reaction with a general primer and a type-specific primer for human papillomavirus Types 16 and 18. Direct sequencing was performed. As a control, 13 normal anal epithelia available from these patients were microdissected. As another control, 21 hemorrhoidal squamous epithelia obtained from a demographically adjusted group were also analyzed. RESULTS: Human papillomavirus Type 16 DNA was present in all 21 anal epidermoid carcinomas. All controls were negative for human papillomavirus DNA. Sequence analysis revealed that 57 percent (12/21) specimens showed two types of sequence variation in the E7 gene. One variant with a single nucleotide change at position 647 (amino acid 29, AAT-->AGT, asparagine to serine) was found in 38 percent (8/21) of the samples. This variant has been detected in cervical cancers from Korean patients: 19 (39 percent) of 49 cervical cancer tissues and 6 (50 percent) of 12 cervical cancer cell lines. Another single nucleotide change at position 645 (amino acid 28, TTA-->TTC, leucine to phenylalanine) was found in 19 percent (4/21) of the samples. These two variants exhibit a change of amino acid affecting the critical sites for Rb binding. CONCLUSION: Human papillomavirus Type 16 was found to be present in all 21 anal epidermoid carcinomas. Furthermore, in the Korean population, the most common sequence variant found in cervical

Anus Neoplasms↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed2006

What common structural features and variations of mammalian P450s are known to date?

Sufficient structural information on mammalian cytochromes P450 has now been published (including seventeen X-ray structures of these enzymes by June 2006) to allow characteristic features of these enzymes to be identified, including: (i) the presence of a common fold, typical of all P450s, (ii) similarities in the positioning of the heme cofactor, (iii) the spatial arrangement of certain structural elements, and (iv) the access/egress paths for substrates and products, (v) probably common orientation in the membrane, (vi) characteristic properties of the active sites with networks of water molecules, (vii) mode of interaction with redox partners and (viii) a certain degree of flexibility of the structure and active site determining the ease with which the enzyme may bind the substrates. As well as facilitating the identification of common features, comparison of the available structures allows differences among the structures to be identified, including variations in: (i) preferred access/egress paths to/from the active site, (ii) the active site volume and (iii) flexible regions. The availability of crystal structures provides opportunities for molecular dynamic simulations, providing data that are apparently complementary to experimental findings but also allow the dynamic behavior of access/egress paths and other dynamic features of the enzymes to be explored.

Amino Acid Sequence↗
PubMed2005

[Clinal variation in populations of the common blue butterfly Polyommatus icarus rott. (Lepidoptera, Lycaenidae)].

Geographical trends in variation of wing pattern characters of the common blue butterfly Polyommatus icarus Rott. have been established. Peripheral populations were shown to be more rich and diverse phenotypically than those of the central parts of the species range. Phenotypic diversity of the populations increased from the center to the periphery of the range. The range boundaries were characterized by strong fluctuations of frequencies of wing pattern phenotypes. Hybrid areas were found on the part of the range examined.

Animals↗
PubMed2004

Genetic association study of PINK1 coding polymorphisms in Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder with a substantial genetic component (which is more pronounced in earlier onset cases). In addition to three well-confirmed PD genes (SNCA, parkin and DJ-1), mutations in the PTEN Induced Kinase (PINK1) gene have recently been identified in families with recessive early onset PD. We tested the hypothesis that three common coding variations (Leu63Leu, Ala340Thr and Asn521Thr) could increase the risk of PD. We performed a case control association study in a series of 91 PD cases (Caucasian of Canadian origin) and 182 normal controls. The patients were largely pre-selected for having an early age of onset (<50 years) and/or a positive family history. Our results did not reveal any evidence of association between PD and any of the three SNPs at the allelic or genotypic levels (p > 0.25). Furthermore, we did not detect a modifying effect for any genotype upon the age of onset in the PD group (p > 0.19). Nevertheless, it remains to be evaluated whether PINK1 variations contribute to the risk of common late onset sporadic PD.

Adult↗
PubMed1989

Association between cilioretinal arteries and juxtapapillary scars.

We examined the relationship of cilioretinal arteries (CRAs) to juxtapapillary chorioretinal scars, along with the developmental significance of the latter in relation to CRA formation. Both eyes of 360 patients were studied. Sixty-eight (18.9%) of these patients had a CRA in at least one eye, 13 of these 68 (19.1%) had one in both. The CRAs were distributed equally between right and left eyes. Two hundred eight patients (57.8%) had a scar in at least one eye; 157 of these (75.5%) had one in both. The presence of a CRA was significantly associated with the presence of a scar. Since both are common developmental variations, this correlation points to a common embryologic formation mechanism.

Ciliary Body↗
PubMed1997

Common genomic variants associated with variation in plasma lipoproteins in young aboriginal Canadians.

We hypothesized that common genomic variants would be associated with variation in lipoprotein phenotypes in young subjects. We determined genotypes of FABP2, PON, APOC3, and APOE in 188 aboriginal Canadians, aged 9 to 17 years. We found that 13 of 32 possible genotype-phenotype associations were significant: (1) the FABP2 codon 54 genotype was associated with variation in plasma triglycerides (P = .045); (2) the PON codon 192 genotype was associated with variation in plasma total and LDL cholesterol and apoB (P = .0099, P = .0088, and P = .016, respectively); (3) the APOC3 insulin-response-element genotype was associated with variation in plasma triglycerides, HDL cholesterol, apoA-I, the total cholesterol to HDL cholesterol ratio, and the apoB to apoA-I ratio (P = .0014, P = .0069, P = .045, P = .0021, and P = .0081, respectively); and (4) the APOE restriction isotype was associated with variation in plasma LDL cholesterol, apoB, the total cholesterol to HDL cholesterol ratio, and the apoB to apoA-I ratio (P = .025, P = .034, P = .045, and P = .047, respectively). The average young age and relative absence of age-dependent secondary environmental factors could have eased the identification of small genetic effects on lipoprotein phenotypes in this study sample.

Adolescent↗