The aim is this study is to compare the longitudinal changes in IQ scores of females and males with fragile X syndrome and controls and to assess the impact on IQ of molecular variations of the FMR‐1 gene in males. Medical records from the child development unit at a university‐affiliated children's hospital were retrospectively reviewed. Chart review yielded 35 males with fragile X (19 with a fully methylated full mutation, 9 with a mosaic pattern, and 7 with a partially unmethylated full mutation) 16 females with fragile X and a full mutation, 9 female controls, and 9 male controls who had repeated standardized IQ testing separated by 7 months to 13 years. The differences between the first and last IQ scores from the same IQ test were compared by t tests and subsequently by analysis of variance. Overall, a significant IQ decline was seen in 10/35 (28%) of fragile X males, 0/9 (0%) of control males, 6/16 (36%) of fragile X females, and 1/9 (11%) of control females. The initial t tests and analysis of variance showed a significant difference in IQ (p = 0.02) between fragile X males and control males but did not show a significant difference between males and females with fragile X syndrome or between fragile X and control females. When an analysis of covariance was carried out with the initial IQ as a covariable, a significant difference persisted between fragile X and control males, with a greater IQ decline in fragile X males. There were limitations in using the same IQ test. A comparison among the molecular subgroups of males yielded a significant IQ decline in 3/9 (33%) of mosaic males, 6/19 (32%) of fully methylated full mutation males, and 1/7 (14%) of partially methylated full mutation males. An analysis of covariance using the initial IQ and the intertest interval as covariables demonstrated significant differences between the fragile X molecular subgroups and the controls. Our findings show that a substantial percentage of both male and female fragile X patients and female control patients demonstrated significant IQ decline. There was a significant differences in the IQ change between fragile X and control males. There were no significant differences between fragile X and female controls. There were also significant differences in IQ decline among males with different molecular patterns compared with controls. Males with a mosaic pattern versus control males had the most significant decline of the molecular subtypes. Although the numbers were limited, there was no significant IQ decline in males with less than 50% methylation of the full mutation. This suggests that a small amount of FMR‐1 protein production, which is often seen in males with less than 50% methylation, protects against significant IQ decline. © 1996 Wiley‐Liss, Inc.

No abstract

Genome-wide association studies (GWAS) of coronary artery disease (CAD) have revealed multiple genetic risk loci. We assessed the association of 47 genome-wide significant single-nucleotide polymorphisms (SNPs) at 43 CAD loci with coronary stenosis in a Pakistani sample comprising 663 clinically ascertained and angiographically confirmed cases. Genotypes were determined using the iPLEX Gold technology. All statistical analyses were performed using R software. Linkage disequilibrium (LD) between significant SNPs was determined using SNAP web portal, and functional annotation of SNPs was performed using the RegulomeDB and Genotype-Tissue Expression (GTEx) databases. Genotyping comparison was made between cases with severe stenosis (≥70%) and mild/minimal stenosis (<30%). Five SNPs demonstrated significant associations: three with additive genetic models PLG/rs4252120 (p=0.0078), KIAA1462/rs2505083 (p=0.005), and SLC22A3/rs2048327 (p=0.045) and two with recessive models SORT1/rs602633 (p=0.005) and UBE2Z/rs46522 (p=0.03). PLG/rs4252120 was in LD with two functional PLG variants (rs4252126 and rs4252135), each with a RegulomeDB score of 1f. Likewise, KIAA1462/rs2505083 was in LD with a functional SNP, KIAA1462/rs3739998, having a RegulomeDB score of 2b. In the GTEx database, KIAA1462/rs2505083, SLC22A3/rs2048327, SORT1/rs602633, and UBE2Z/rs46522 SNPs were found to be expression quantitative trait loci (eQTLs) in CAD-associated tissues. In conclusion, five genome-wide significant SNPs previously reported in European GWAS were replicated in the Pakistani sample. Further association studies on larger non-European populations are needed to understand the worldwide genetic architecture of CAD.

Coronary artery disease (CAD) is a complex disorder involving both genetic and non-genetic factors. Genome-wide association studies (GWAS) have identified hundreds of single nucleotides polymorphisms (SNPs) tagging over > 40 CAD risk loci. We hypothesized that some non-coding variants might directly regulate the gene expression rather than tagging a nearby locus. We used RegulomeDB to examine regulatory functions of 58 SNPs identified in two GWAS and those SNPs in linkage disequilibrium (LD) (r2 ≥ 0.80) with the GWAS SNPs. Of the tested 1200 SNPs, 858 returned scores of 1–6 by RegulomeDB. Of these 858 SNPs, 97 were predicted to have regulatory functions with RegulomeDB score of < 3. Notably, only 8 of the 97 predicted regulatory variants were genome-wide significant SNPs (LIPA/rs2246833, RegulomeDB score = 1b; ZC3HC1/rs11556924, CYP17A1-CNNM2-NT5C2/rs12413409, APOE-APOC1/rs2075650 and UBE2Z/rs46522, each with a RegulomeDB score = 1f; ZNF259-APOA5-APOA1/rs964184, SMG6/rs2281727 and COL4A1-COL4A2/rs4773144, each with a RegulomeDB score = 2b). The remainder 89 functional SNPs were in linkage disequilibrium with GWAS SNPs. This study supports the hypothesis that some of the non-coding variants are true signals via regulation of gene expression at transcription level. Our study indicates that RegulomeDB is a useful database to examine the putative functions of large number of genetic variants and it may help to identify a true association among multiple tagged SNPs in a complex disease, such as CAD.Database URLs http://www.regulomedb.org/; https://www.broadinstitute.org/mpg/snap/