Depression disorders are a clinically heterogeneous disease group. Their development is to a substantial extent underlain by dysfunction of the serotonin system, in particular, disturbed serotonin transport. The heterogeneity of depressions is associated, among other factors, with the age at disease onset. Allele polymorphism of the serotonin transporter (5-HTT) gene was tested for association with age at disease onset, clinical signs, and anxiety-related traits of depression patients. A sample included 77 patients (mean age 61.2 +/- 8.8 years) with late-onset depression (LOD, mean age at onset 56.58 +/- 9.7 years) and 74 patients (mean age 31.0 +/- 11.8 years) with early-onset depression (EOD, mean age at onset 23.9 +/- 7.4 years). In genotype frequency distribution of two 5-HTT gene polymorphism, the LOD and EOD groups did not differ from each other (chi 2 = 0.33, P = 0.85 for VNTR-17; chi 2 = 3.33, P = 0.19 for HTTLPR) and from a control group (chi 2 = 0.34, P = 0.84 for VNTR-17; chi 2 = 2.1, P = 0.35 for HTTLPR). In either group, patients differing in VNTR-17 and HTTLPR genotypes did not differ in psychological traits and, in particular, in anxiety-related traits. In the case of the HTTLPR polymorphism, LOD patients with genotype ss tended to display less severe neuroticism (t = 2.03, P = 0.0507) and scored significantly less on the Hamilton depression scale (t = 2.19, P = 0.039). Thus, the 5-HTT gene polymorphisms do not affect the risk of depression but is possibly associated with specific clinical signs of the disease, at least in elderly patients.
PURPOSE: Benign rolandic epilepsy (BRE) is considered a genetically determined idiopathic partial epilepsy. We analyzed a large sample of twins from four international twin registers to probe the genetics of BRE. We also aim to synthesize the apparently conflicting family and twin data into a model of BRE etiology. METHODS: Large population-based twin registries of epilepsies from Odense (Denmark), Richmond, Virginia (United States), and Oslo (Norway) were reviewed for BRE cases and added to our Australian twin data. Diagnosis of classic BRE was based on electroclinical criteria with normal neurologic development. Cases with a compatible electroclinical picture but abnormal neurologic development were termed non-classic BRE. RESULTS: Eighteen twin pairs were identified (10 monozygous; eight dizygous) of whom at least one twin was diagnosed with classic BRE among a total sample of 1,952 twin pairs validated for seizures, and all were discordant for BRE. The estimated monozygous pairwise concordance for BRE in this sample was 0.0 [95% confidence interval (CI), 0.0-0.3). Four twin pairs (one monozygous, three dizygous) had non-classic BRE, and all co-twins had seizures. CONCLUSIONS: The twin data showing an absence of any concordant twin pairs with classic BRE suggest that noninherited factors are of major importance in BRE. Modelling the data shows that the familial occurrence of centrotemporal spikes makes only a minor contribution to the familial aggregation of BRE. Genetic factors are probably more important in non-classic BRE. The etiology and mode(s) of inheritance of BRE are much more complicated than initially conceptualized.
The breast-ovary cancer-family syndrome is a dominant predisposition to cancer of the breast and ovaries which has been mapped to chromosome region 17q12-q21. The majority, but not all, of breast-ovary cancer families show linkage to this susceptibility locus, designated BRCA1. We report here the results of a linkage analysis of 145 families with both breast and ovarian cancer. These families contain either a total of three or more cases of early-onset (before age 60 years) breast cancer or ovarian cancer. All families contained at least one case of ovarian cancer. Overall, an estimated 76% of the 145 families are linked to the BRCA1 locus. None of the 13 families with cases of male breast cancer appear to be linked, but it is estimated that 92% (95% confidence interval 76%-100%) of families with no male breast cancer and with two or more ovarian cancers are linked to BRCA1. These data suggest that the breast-ovarian cancer-family syndrome is genetically heterogeneous. However, the large majority of families with early-onset breast cancer and with two or more cases of ovarian cancer are likely to be due to BRCA1 mutations.
It is widely believed that, if a genetic marker shows a transmission distortion in patients by the transmission/disequilibrium test (TDT), then a transmission distortion in healthy siblings would be seen in the opposite direction. This is also the case in a complex disease. Furthermore, it has been suggested that replacing the McNemar statistics of the TDT with a test of heterogeneity between transmissions to affected and unaffected children could increase the power to detect disease association. To test these two hypotheses empirically, we analyzed the transmission of HLA-DQA1-DQB1 haplotypes in 526 Norwegian families with type 1 diabetic children and healthy siblings, since some DQA1-DQB1 haplotypes represent major genetic risk factors for type 1 diabetes. Despite the strong positive and negative disease associations with particular DQ haplotypes, we observed no significant deviation from 50% for transmission to healthy siblings. This could be explained by the low penetrance of susceptibility alleles, together with the fact that IDDM loci also harbor strongly protective alleles that can override the risk contributed by other loci. Our results suggest that, in genetically complex diseases, detectable distortion in transmission to healthy siblings should not be expected. Furthermore, the original TDT seems more powerful than a heterogeneity test.
Autosomal recessive congenital ichthyosis (ARCI) is a rare, clinically and genetically heterogeneous genodermatosis. One gene (transglutaminase 1, on 14q11) and one additional locus (on 2q33-35, with an unidentified gene) have been shown to be associated with a lamellar, nonerythrodermic type of ARCI. We performed a genomewide scan, with 370 highly polymorphic microsatellite markers, on five affected individuals from one large Finnish family with nonerythrodermic, nonlamellar ARCI. The only evidence for linkage emerged from markers in a 6.0-cM region on chromosome 19p13.1-2. The maximum two-point LOD score of 7.33 was obtained with the locus D19S252, and multipoint likelihood calculations gave a maximum location score of 5.2. The affected individuals share two common core haplotypes, which makes compound heterozygosity possible. The novel disease locus is the third locus linked to ARCI, supporting previous evidence for genetic heterogeneity of ARCI. This is also the first locus for a nonlamellar, nonerythrodermic phenotype of ARCI.
Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for.
To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts.
A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity.
We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P?=?0.00016; rs10931481: P?=?0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-?B1 and IL23A genes in the UK and Italian cohorts respectively.
Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.
Cites: Bioinformatics. 2005 Jan 15;21(2):263-515297300
A susceptibility locus for psoriasis, PSORS4, has been mapped to chromosome 1q21 in the region of the epidermal differentiation complex. The region has been refined to a 115 kb interval around the loricrin (LOR) gene. However, no evidence of association between polymorphisms in the LOR gene and psoriasis has been found. Therefore, we have analysed association to three candidate gene clusters of the region, the S100, small proline-rich protein (SPRR) and PGLYRP (peptidoglycan recognition protein) genes, which all contain functionally interesting psoriasis candidate genes. In previous studies, the SPRR and S100 genes have shown altered expression in psoriasis. Also polymorphisms in the PGLYRP genes have shown to be associated with psoriasis. We genotyped altogether 29 single nucleotide polymorphisms (SNPs) in 255 Finnish psoriasis families and analysed association with psoriasis using transmission disequilibrium test. A five-SNP haplotype of PGLYRP SNPs associated significantly with psoriasis. There was also suggestive evidence of association to SPRR gene locus in Finnish families. To confirm the putative associations, selected SNPs were genotyped also in a family collection of Swedish and Irish patients. The families supported association to the two gene regions, but there was also evidence of allelic heterogeneity.
We describe an autosomal-dominant locus for Restless Legs Syndrome (RLS) in a French-Canadian (FC) pedigree. Genome-wide microsatellite scan and linkage analysis were used in this study. The locus maps to chromosome 16p12.1 and spans 1.18 Mega bases. The maximum multipoint LOD scores are of 3.5 over the total of 10 markers. Evidence for the same locus was also found in a smaller FC pedigree sime095. The analysis of the sequence of 8 annotated genes within the region did not reveal any pathogenic mutations. Copy number variation and karyotype analyses did not reveal any chromosomal abnormality in the region. Further analyses of the region are necessary to find the genetic cause of RLS in this family.
Using Swedish nationwide registry data, the authors investigated the correlation of genetic and environmental risk factors in the etiology of drug abuse as ascertained from medical and criminal registries by modeling twin and sibling data. Medical drug abuse was defined using public inpatient and outpatient records, while criminal drug abuse was ascertained through legal records. Twin, full and half sibling pairs were obtained from the national twin and genealogical registers. Information about sibling pair residence within the same household was obtained from Statistics Sweden. Standard bivariate genetic structural equation modeling was applied to the population-based data on drug abuse ascertained through medical and crime registries, using OpenMx. Analyses of all possible pairs of twins (MZ: N = 4482; DZ: N = 9838 pairs), full- (N = 1,278,086) and half-siblings (paternal: N = 7767; maternal N = 70,553) who grew up together suggested that factors explaining familial resemblance for drug abuse as defined through medical or criminal registries were mostly the same. Results showed substantial heritability and moderate contributions of shared environmental factors to drug abuse; both were higher in males versus females, and higher for drug abuse ascertained through criminal than medical records. Because of the low prevalence of both assessments of drug abuse, having access to population data was crucial to obtain stable estimates. Using objective registry data, the authors found that drug abuse-whether ascertained through medical versus criminal records-was highly heritable. Furthermore, shared environmental factors contributed significantly to the liability of drug abuse. Genetic and shared environmental risk factors for these two forms of drug abuse were highly correlated.
Cites: Proc Assoc Am Physicians. 1999 Mar-Apr;111(2):109-1810220805
Cites: Am J Psychiatry. 2014 Feb;171(2):209-1724077613
OBJECTIVE: The purpose of the study was to carry out a candidate gene analysis in families with familial thoracic aortic aneurysms and dissections. METHODS: The study material consisted of 11 Finnish families (with 115 members genotyped) who underwent echocardiographic examination for measurement of the aortic root diameter. Selected candidate genes included the loci for Marfan and Ehlers-Danlos syndromes, the genes of matrix metalloproteinases 3 and 9 and tissue inhibitor of metalloproteinase 2 as well two loci on the chromosomes 5q13-14 and 11q23.2-q24, previously found to be linked to the disease. RESULTS: The chromosomal locus 5q13-14 was linked to the disease risk (nonparametric linkage score 3.0, P =.005) confirming the previous linkage. Other candidate genes and loci were excluded as major loci in these families. CONCLUSIONS: The identification of the gene at chromosomal location 5q13-14 causing the development of such diseases would give us important knowledge on the pathogenesis of the disease and enable the identification of subjects at risk. This in turn would lead to appropriate treatment before the occurrence of fatal complications and, likely, to the development of new treatment methods.