Showing papers by "Stephan Ripke published in 2008"

PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome.

Abstract: We identified association of restless legs syndrome (RLS) with PTPRD at 9p23-24 in 2,458 affected individuals and 4,749 controls from Germany, Austria, Czechia and Canada. Two independent SNPs in the 5' UTR of splice variants expressed predominantly in the central nervous system showed highly significant P values (rs4626664, P(nominal/lambda corrected) = 5.91 x 10(-10), odds ratio (OR) = 1.44; rs1975197, P(nominal/lambda corrected) = 5.81 x 10(-9), OR = 1.31). This work identifies PTPRD as the fourth genome-wide significant locus for RLS.

IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations

Abstract: Multiple sclerosis (MS) is the most common chronic inflammatory neurologic disorder diagnosed in young adults and, due to its chronic course, is responsible for a substantial economic burden. MS is considered to be a multifactorial disease in which both genetic and environmental factors intervene. The well-established human leukocyte antigen (HLA) association does not completely explain the genetic impact on disease susceptibility. However, identification and validation of non-HLA-genes conferring susceptibility to MS has proven to be difficult probably because of the small individual contribution of each of these genes. Recently, associations with two single nucleotide polymorphisms (SNPs) in the IL2RA gene (rs12722489, rs2104286) and one SNP in the IL7RA gene (rs6897932) have been reported by several groups. These three SNPs were genotyped in a French and a German population of MS patients using the hME assay by the matrix-assisted laser desorption/ionization time of flight technology (Sequenom, San Diego, CA, USA). We show that these SNPs do contribute to the risk of MS in these two unrelated European MS patient populations with odds ratios varying from 1.1 to 1.5. The discovery and validation of new genetic risk factors in independent populations may help toward the understanding of MS pathogenesis by providing valuable information on biological pathways to be investigated.

Genetic Variation in Soluble Epoxide Hydrolase (EPHX2) Is Associated With an Increased Risk of Ischemic Stroke in White Europeans

Abstract: Background and Purpose— Genetic variation in the EPHX2 gene region has been reported to influence susceptibility to ischemic stroke in blacks. We assessed the role of this gene region in white Europeans and performed analyses with regard to stroke subtypes. Methods— Twenty-six single nucleotide polymorphisms in the EPHX2 gene region were genotyped in 601 patients with ischemic stroke and 736 matched controls. Cases were subtyped according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system. Analyses were done on single markers and haplotypes using a sliding-window approach. Results— Three single nucleotide polymorphisms showed associations with an increased risk for ischemic stroke (allelic models; all P≤0.01). One of them retained statistical significance after correction for multiple testing. Associations were observed with large-vessel stroke and stroke of undetermined etiology but not with other stroke subtypes. Conclusions— Our findings confirm and extend previous studie...

Genetic Markers Within Glutamate Receptors Associated With Antidepressant Treatment-Emergent Suicidal Ideation

Abstract: ajp.psychiatryonline.org cause of space limitations, we were unable to include several key aspects of clinical care. As educators as well as clinicians, we consistently remind those who we teach about the importance of close communication with school personnel regarding the functioning of our patients, wherever they may be on the spectrum of risk to others. In hindsight, including content that stressed the importance of close communication between the clinician and school personnel could have strengthened our article. We agree that the use of a systematic assessment of violence risk is essential. However, it is our opinion that a reductionistic tendency of systems to rely on only one approach of risk assessment—as we have frequently seen in our own clinical practices—often does not lead to optimal placements for young, school-age patients.

Evidence for associations between PDE4D polymorphisms and a subtype of neuroticism. [Letter to the editor]

Abstract: Recently, Shifman et al. reported the first genomewide association analysis for extreme scores of the personality trait neuroticism measured by the revised form of Eysenck’s personality questionnaire (EPQ-R) using pooled DNA. One single nucleotide polymorphism (SNP) of the initial whole genome analysis, rs702543, located in an intron of the cAMP-specific phosphodiesterase 4D (PDE4D) gene could be replicated in a separate sample of the same cohort and in independent families. PDE4D is mapping on chromosome 5q11.2-5q12.1 and spans a region of more than 615 000 bp. A role of the PDE4D gene for depression has been suggested from results with the cAMPphosphodiesterase inhibitor, rolipram, exhibiting antidepressant effects in patients, which appears to be essentially mediated by PDE4D. Based on these findings, we sought to further elucidate the effects of PDE4D on personality traits related to neuroticism in healthy subjects as well as in patients with major depression. Data are available in 366 healthy subjects and 163 inpatients with major depression participating in the Munich Antidepressant Response Signature (MARS) project. Healthy subjects were examined with a modified version of the Munich-Composite International Diagnostic Interview (DIA-X/M-CIDI) to exclude a lifetime history of mental Axis I disorders according to criteria of the Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Patients’ diagnosis was ascertained by trained psychiatrists applying DSM-IV criteria, and patients filled in the personality questionnaires prior to discharge with current psychopathology, evaluated with the Hamilton Scales for Depression and Anxiety. The majority of patients was in clinical remission at the time of personality assessment; nevertheless, test scores were additionally corrected for current depression and anxiety. One hundred and twenty-eight SNPs covering the PDE4D region (±10 kb) with an average marker distance of B5 kb were genotyped in healthy subjects using Illumina Bead Chips HumanHap300, 300 k and Human-1, 100 k (Illumina Inc., San Diego, CA, USA). Personality was evaluated in terms of neuroticism (NEU; EPQ-R) and harm avoidance (HA; Cloninger’s Tridimensional Personality Questionnaire TPQ), which is closely related to neuroticism (r = 0.70) and can be subdivided into four subscales (HA1, anticipatory worries and pessimism; HA2, fear of uncertainty; HA3, shyness with strangers; HA4, fatigability and asthenia). Standardized residuals of the personality traits (corrected for age, gender, in patients additionally for scores of the Hamilton scales for depression and the Hamilton scales for anxiety) were analyzed using analysis of variance, testing a genotypic and allelic model of inheritance. Effect sizes are reported as Cohen’s f. A case–control analysis was performed using Fisher’s exact test. Nominal P-values were corrected for multiple comparisons according to Westfall and Young using 10 000 permutations. We found nominal associations for 38 SNPs with NEU, HA and HA subscales. After correction for multiple testing, the association between the intronic SNP rs1971940 and HA4 (‘Fatigability and asthenia’) remained significant (pnominal = 0.0004, pcorrected = 0.03; f = 0.13, suggesting a small effect; see Figure 1). rs702543, reported by Shifman et al. to be associated with extremes of NEU in three independent samples, showed a nominal association only with HA2 (pnominal = 0.048, ‘Fear of uncertainty’), which did not withstand correction for multiple testing. No other associations with rs702543 emerged. We reanalyzed our data using the same procedure as Shifman et al. to obtain extreme scores of personality, but failed to find any improvement of nominal P-values, presumably due to absence of nonlinear effects. In addition, we reanalyzed 38 nominally significant SNPs (P < 0.05) in the patients. One intronic SNP (rs1870077) showed nominal associations with HA2 (pnominal = 0.01, ‘Fear of uncertainty’) and HA3 (pnominal = 0.001, ‘Shyness with strangers’) as well as with HA (pnominal = 0.01). The association with HA3 remained significant after correction (pcorrected = 0.04; f = 0.30, suggesting a medium effect; see Figure 1). No effects were found for rs702543. The case–control association analysis revealed significant effects for rs1971940 (pnominal = 0.02) and rs2409627 (pnominal = 0.02, both in linkage disequilibrium (r = 0.5)) which, however, did not remain significant after correction for multiple testing. The associated SNPs (rs1971940 and rs1870077) are not in linkage disequilibrium neither to each other (r = 0.02) nor to the SNP reported by Shifmanet al. (r = 0.001 and 0.03, respectively). Several intronic SNPs in PDE4D showed nominally significant associations with NEU, HA and HA subscales in healthy subjects with one SNP, rs1971940, remaining associated with HA4 ‘Fatigability and asthenia’ after correction for multiple testing. According to HapMap data, rs1971940 is located in a linkage Molecular Psychiatry (2008) 13, 831–832 & 2008 Nature Publishing Group All rights reserved 1359-4184/08 $30.00