Several copy number variants have been associated with neuropsychiatric disorders and these variants have been shown to also influence cognitive abilities in carriers unaffected by psychiatric disorders. Previously, we associated the 15q11.2(BP1-BP2) deletion with specific learning disabilities and a larger corpus callosum. Here we investigate, in a much larger sample, the effect of the 15q11.2(BP1-BP2) deletion on cognitive, structural and functional correlates of dyslexia and dyscalculia. We report that the deletion confers greatest risk of the combined phenotype of dyslexia and dyscalculia. We also show that the deletion associates with a smaller left fusiform gyrus. Moreover, tailored functional magnetic resonance imaging experiments using phonological lexical decision and multiplication verification tasks demonstrate altered activation in the left fusiform and the left angular gyri in carriers. Thus, by using convergent evidence from neuropsychological testing, and structural and functional neuroimaging, we show that the 15q11.2(BP1-BP2) deletion affects cognitive, structural and functional correlates of both dyslexia and dyscalculia.
Since Dr. Fogh-Andersen's legendary 1942 thesis, the Danish facial cleft population has been one of the most extensively studied in terms of epidemiology and genetic-epidemiology. The etiology of cleft lip and/or palate (CLP) is still largely an enigma, and different results concerning environmental and genetic risk factors are obtained in different countries and regions. This may be due to etiological heterogeneity between settings. Therefore, an in-depth studied area with an ethnically homogeneous population, such as Denmark, has provided one of the best opportunities for progress in CLP etiological research. The present review summarizes epidemiological and genetic-epidemiological studies conducted in the 20th century Danish facial cleft population. Furthermore, analyses of sex differences, time trends and seasonality for more than 7000 CLP cases born in Denmark in the period 1936 to 1987 are presented. The review also points toward the excellent opportunities for continued etiological CLP research in Denmark in the 21st century using already established resources and an on-going prospective cohort study of 100,000 pregnant women.
Numerous linkage studies have indicated chromosome 18q21-22 as a locus of importance for blood pressure regulation. This locus harbors the neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) gene, which is instrumental for the regulation of the amiloride-sensitive epithelial sodium channel (ENaC). In a linkage study of 16 markers (including two single nucleotide polymorphism markers located within the NEDD4L gene) on chromosome 18 between 70-104 cM and ambulatory blood pressure (ABP), in 118 families, the strongest evidence of linkage was found for 24 h and day-time systolic ABP at the NEDD4L locus (82.25 cM) (P=0.0014). In a large population sample (n=4001), we subsequently showed that a NEDD4L gene variant (rs4149601), which by alternative splicing leads to varying expression of a functionally crucial C2 domain, was associated with diastolic blood pressure (DBP) (P=0.03) and DBP progression over time (P=0.04). A genotype combination of the rs4149601 and an intronic NEDD4L marker (rs2288774) was associated with systolic blood pressure (SBP) (P=0.01), DBP (P=0.04), and progression of both SBP (P=0.03) and DBP (P=0.05) over time. A quantitative transmission disequilibrium test in the family material of the rs4149601 supported this NEDD4L variant as being at least partially causative of the linkage result. In conclusion, our findings suggest that the chromosome 18 linkage peak at 82.25 cM is explained by genetic NEDD4L variation affecting cross-sectional and longitudinal blood pressure, possibly as a consequence of altered NEDD4L interaction with ENaC.
The promoter sequence variant -480T in the hepatic lipase gene (LIPC) has been shown to be significantly associated with low post-heparin hepatic lipase activity. Some studies have also found that the -480T variant is associated with elevation in plasma HDL cholesterol. We tested for associations of LIPC -480T with plasma lipoprotein traits in samples taken from three distinct Canadian populations: 657 Alberta Hutterites, 328 Ontario Oji-Cree and 210 Keewatin Inuit. Plasma HL activity was not available for analyses. The LIPC -480T allele frequencies in these three groups, respectively, were 0.219, 0.527 and 0.383, and the prevalence of LIPC -480T/T homozygotes was, respectively, 0.042, 0.274 and 0.167. No significant association was found between LIPC -480T and plasma HDL cholesterol or apolipoprotein AI concentration, after adjusting for covariates including gender and body mass index. There was no consistent relationship between the population mean plasma HDL cholesterol concentration and the population LIPC -480T frequency. Our findings are consistent with the idea that the common promoter variation in LIPC, which has been reported to be associated with variation in post heparin HL activity and HDL triglyceride concentration, is not always associated with variation in plasma HDL cholesterol concentration, possibly due to yet unspecified environmental or genetic factors.
Based on analysis of variation at ten allozyme loci in three age groups (25-35, 40-80, and more than 100 years of age) of plants and in seed embryos, demographic dynamics of the gene pools was studied in a small (60.5 ha) isolated relict population of chalk pine Pinus sylvestris var. cretacea Kalenicz. ex Kom. from the steppe zone of Ukraine. The observed grenotype proportions in these tree groups were shown to fit Hardy-Weinberg expectations, while in the embryos of their seeds, an excess of homozygotes was observed at five to nine loci. The mean observed heterozygosity in the sample of old (> 100 years of age) trees (H(O) = 0.225) was substantially lower than in trees of the two other age groups (H(O) = 0.307; 0.311), but significantly higher than in the corresponding embryo samples (H(O) = 0.183-0.207). No allele and genotype heterogeneity of the maternal trees and embryos of their seeds was found. However, heterogeneity was high when the progeny of trees of different ages, particularly in pairs with old trees, were compared.
In anticipation of the sequencing of the human genome and description of the human proteome, the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik) was initiated in 2002. AGES-Reykjavik was designed to examine risk factors, including genetic susceptibility and gene/environment interaction, in relation to disease and disability in old age. The study is multidisciplinary, providing detailed phenotypes related to the cardiovascular, neurocognitive (including sensory), and musculoskeletal systems, and to body composition and metabolic regulation. Relevant quantitative traits, subclinical indicators of disease, and medical diagnoses are identified by using biomarkers, imaging, and other physiologic indicators. The AGES-Reykjavik sample is drawn from an established population-based cohort, the Reykjavik Study. This cohort of men and women born between 1907 and 1935 has been followed in Iceland since 1967 by the Icelandic Heart Association. The AGES-Reykjavik cohort, with cardiovascular risk factor assessments earlier in life and detailed late-life phenotypes of quantitative traits, will create a comprehensive study of aging nested in a relatively genetically homogeneous older population. This approach should facilitate identification of genetic factors that contribute to healthy aging as well as the chronic conditions common in old age.
The genetic analysis of the variants of human immunodeficiency virus of type 1 (HIV-1), circulating among drug addicts in Moscow and Moscow Province, has been carried out. The serological analysis of 122 blood specimens taken from HIV-infected drug addicts, residing in Moscow and 22 settlements of the Moscow region, has shown that in this region HIV-1 variant of subtype A spreads among drug addicts. These data have been confirmed by the results of the analysis of 44 specimens, made with the use of the method of the heteroduplex mobility assay for gene env. As revealed in this study, HIV-1 variants spreading at present among drug addicts in Moscow and the Moscow region are genetically related to viruses of subtype A, detected earlier in this group of risk in other regions of Russia, the Ukraine, Belarus and other countries of Eastern Europe.
One of the leading causes of blindness in the world is glaucoma. The most common form is primary open-angle glaucoma (POAG). The only gene identified so far as being associated with POAG is the MYOC gene; 2-4% of the patients have been reported to carry mutations in this gene. Exfoliative glaucoma is a secondary glaucoma, in which one of the symptoms is exfoliations on the lens capsule and anterior segment of the eye. No gene has been identified as being associated with this variant. The aim of the present study was to analyze Swedish patient material for allelic variants and mutations in the coding region of the MYOC gene. Two hundred patients with POAG and 200 with exfoliative glaucoma were analyzed using enzymatic cleavage assay and denaturing high-performance liquid chromatography (dHPLC). An age-matched control group (n = 200), in whom glaucoma had been excluded, was also analyzed using dHPLC. Eight allele variants were identified, two of which were determined to be disease-causing mutations. These two disease-causing mutations were only found in POAG patients, indicating a prevalence of 1% in this patient group. This frequency is lower than that reported in other studies of other populations. No disease-causing mutations were found in the exfoliative glaucoma patients, indicating a fundamentally different genetic basis for that glaucoma variant.