A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus.

Recent genome-wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio (OR)=0.81, 95% confidence interval (95% CI) = 0.76-0.86, P(combined) = 3.5 × 10(-10)), located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment known to be involved in HL pathogenesis. This meta-analysis also notes associations between previously published loci at 2p16, 5q31, 6p31, 8q24 and 10p14 and HL subtypes. We conclude that our data suggest a link between the 19p13.3 locus, including TCF3, and HL risk.

Genome-wide association study of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.

Genome-wide association study of Tourette's syndrome.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Lift/transfer and technical aids for persons with severe acquired brain injury. An inventory of problems.

A questionnaire about assistive devices for lift and transfer was distributed to all individuals evaluated at the Solberga Project outpatient service unit, a regional centre for long-term follow-up of severely brain injured persons in the Greater Stockholm area. The target group was 60 severely brain injured adults, of whom 57 (30 women and 27 men) answered a questionnaire created by one of the authors. The causes of injury in the study population were trauma (n = 27), cerebrovascular accident (n = 19), anoxia (n = 10) and other (n = 1). Thirty-two persons were quadriplegic after the injury and 21 were hemiplegic. More than half (33/57) reported problems with all five defined lift and transfer situations. Most (42/44) reported problems getting in and out of their wheelchairs. Technical aids were seldom used; 24 persons did not use any aids at all. The most commonly used aid was an adjustable bed. Most of the technical aids were used when the individual also had personal assistance. The persons who managed lift and transfer by themselves used few aids. It is reasonable to assume that severely brain injured individuals would be involved in more activities if they used technical aids more readily.

Properties of person hoist spreader bars and their influence on sitting/lifting position.

The purpose of this study is to analyse mechanical lifts with regard to how the spreader bar design, e.g. frontal length, height and sagittal depth, affects sitting positions and safety during lift and transfer. The seven spreader bars available on the Swedish market had two-point to four-point suspensions. Twelve subjects were photographed individually sitting in each of three types of sling: divided, one-piece with divided leg support, and one-piece. All the slings had significant effects on all specific sitting aspects. However, the spreader bar design only affected the sitting position in the hoist. A long (0.62 m) spreader bar gave a relatively upright sitting position. A deep (0.18 m) spreader bar gave a backward inclination. For all specific sitting aspects, there was a significant interaction between slings and spreader bars. This study demonstrates that the design of the spreader bar, as well as that of the sling, is of decisive importance for the sitting position during lifting.

Hoists for locomotor disability--Properties of the person-carrying section and biomechanics of sitting positions.

The purpose of this study was to make an inventory of the slings available for person hoists, to describe them and to carry out biomechanical analyses of the sitting positions in different slings. On the Swedish market 18 different slings were available. Nine were photographed with a subject sitting in them. The sagittal lengths of the supporting parts of the slings varied between 0.10 m and 1.0 m. The risk of falling through was considered largest in divided slings, but even in one-piece slings with divided leg supports, the person lifted can most probably slip through inadvertently. Almost all the slings gave a backward-inclined sitting position. However, in one of the slings the trunk inclination was small and the seat was slightly forward-downward inclined, giving a risk of falling/sliding forwards. Some of the slings entailed a trunk thigh angle smaller than 90 degrees, perhaps a problem for patients with hip pain and reduced hip flexion. Given the great variety of slings available, it seems important to work for relevant instructions and information about their use.