The objective was to test the hypothesis that a described association between homozygosity for a 50bp deletion in the SOD1 promoter 1684bp upstream of the SOD1 ATG and an increased age of onset in SALS can be replicated in additional SALS and control sample sets from other populations. Our second objective was to examine whether this deletion attenuates expression of the SOD1 gene. Genomic DNA from more than 1200 SALS cases from Ireland, Scotland, Quebec and the USA was genotyped for the 50bp SOD1 promoter deletion. Reporter gene expression analysis, electrophoretic mobility shift assays and chromatin immunoprecipitation studies were utilized to examine the functional effects of the deletion. The genetic association for homozygosity for the promoter deletion with an increased age of symptom onset was confirmed overall in this further study (p=0.032), although it was only statistically significant in the Irish subset, and remained highly significant in the combined set of all cohorts (p=0.001). Functional studies demonstrated that this polymorphism reduces the activity of the SOD1 promoter by approximately 50%. In addition we revealed that the transcription factor SP1 binds within the 50bp deletion region in vitro and in vivo. Our findings suggest the hypothesis that this deletion reduces expression of the SOD1 gene and that levels of the SOD1 protein may modify the phenotype of SALS within selected populations.
In contrast to many phenotypes that have been studied using twin designs, substance use shows considerable evidence of environmental influence. Accordingly, specifying the relevant environments and understanding the nature of their effects is an important research priority. Twin studies also have demonstrated that the importance of genetic and environmental influences varies across development for a variety of behavioral outcomes, including substance use. Here, we report analyses exploring moderating effects associated with parenting and peer characteristics on adolescent smoking and drinking, measured at ages 14 and 17. We find significant evidence of moderating effects associated with two dimensions of parenting (parental monitoring and time spent in activities with parents) on adolescent smoking, measured at two time points across development, but no moderating effects on adolescent drinking. Genetic influences on smoking increased, and common environmental effects decreased, as adolescents reported less parental monitoring and spending more time with their parents. Conversely, we find evidence that adolescent drinking is more strongly influenced by peer characteristics. The importance of genetic predispositions was increased among adolescents who reported more friends who used alcohol. These analyses illustrate the importance of incorporating measured aspects of the environment into genetically informative twin models to begin to understand how specific environments are related to various outcomes. Furthermore, they illustrate the importance of using a developmental perspective to understand how specific influences may vary across different ages, and across different phenotypes.
1] Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.  Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. .
Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.
To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
Candidate-gene association studies in rheumatoid arthritis (RA) have lead to encouraging yet apparently inconsistent results. One explanation for the inconsistency is insufficient power to detect modest effects in the context of a low prior probability of a true effect. To overcome this limitation, we selected alleles with an increased probability of a disease association, on the basis of a review of the literature on RA and other autoimmune diseases, and tested them for association with RA susceptibility in a sample collection powered to detect modest genetic effects. We tested 17 alleles from 14 genes in 2,370 RA cases and 1,757 controls from the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) collections. We found strong evidence of an association of PTPN22 with the development of anti-citrulline antibody-positive RA (odds ratio [OR] 1.49; P=.00002), using previously untested EIRA samples. We provide support for an association of CTLA4 (CT60 allele, OR 1.23; P=.001) and PADI4 (PADI4_94, OR 1.24; P=.001) with the development of RA, but only in the NARAC cohort. The CTLA4 association is stronger in patients with RA from both cohorts who are seropositive for anti-citrulline antibodies (P=.0006). Exploration of our data set with clinically relevant subsets of RA reveals that PTPN22 is associated with an earlier age at disease onset (P=.004) and that PTPN22 has a stronger effect in males than in females (P=.03). A meta-analysis failed to demonstrate an association of the remaining alleles with RA susceptibility, suggesting that the previously published associations may represent false-positive results. Given the strong statistical power to replicate a true-positive association in this study, our results provide support for PTPN22, CTLA4, and PADI4 as RA susceptibility genes and demonstrate novel associations with clinically relevant subsets of RA.
Large case-control genome-wide association studies primarily expose common variants contributing to disease pathogenesis with modest effects. Thus, alternative strategies are needed to tackle rare, possibly more penetrant alleles. One strategy is to use special populations with a founder effect and isolation, resulting in allelic enrichment. For multiple sclerosis such a unique setting is reported in Southern Ostrobothnia in Finland, where the prevalence and familial occurrence of multiple sclerosis (MS) are exceptionally high. Here, we have studied one of the best replicated MS loci, 5p, and monitored for haplotypes shared among 72 regional MS cases, the majority of which are genealogically distantly related. The haplotype analysis over the 45 Mb region, covering the linkage peak identified in Finnish MS families, revealed only modest association at IL7R (P = 0.04), recently implicated in MS, whereas most significant association was found with one haplotype covering the C7-FLJ40243 locus (P = 0.0001), 5.1 Mb centromeric of IL7R. The finding was validated in an independent sample from the isolate and resulted in an odds ratio of 2.73 (P = 0.000003) in the combined data set. The identified relatively rare risk haplotype contains C7 (complement component 7), an important player of the innate immune system. Suggestive association with alleles of the region was seen also in more heterogeneous populations. Interestingly, also the complement activity correlated with the identified risk haplotype. These results suggest that the MS predisposing locus on 5p is more complex than assumed and exemplify power of population isolates in the identification of rare disease alleles.
Cites: Am J Hum Genet. 2001 Apr;68(4):978-8911254454
Cites: Ann Neurol. 2001 Jul;50(1):121-711456302
Cites: Ann Med. 2001 Sep;33(6):410-2111585102
Cites: J Immunol. 2002 Jan 1;168(1):458-6511751993
Cites: J Immunol. 2002 May 1;168(9):4293-30011970970
Cites: Glia. 2003 Jun;42(4):417-2312730962
Cites: Am J Hum Genet. 2003 Nov;73(5):1162-914574645