C. M. van Duijn

Meta-analyses of genetic studies on major depressive disorder

The genetic basis of major depressive disorder (MDD) has been investigated extensively, but the identification of MDD genes has been hampered by conflicting results from underpowered studies. We review all MDD case–control genetic association studies published before June 2007 and perform meta-analyses for polymorphisms that had been investigated in at least three studies. The study selection and data extraction were performed in duplicate by two independent investigators. The 183 papers that met our criteria studied 393 polymorphisms in 102 genes. Twenty-two polymorphisms (6%) were investigated in at least three studies. Seven polymorphisms had been evaluated in previous meta-analyses, 5 of these had new data available. Hence, we performed meta-analyses for 20 polymorphisms in 18 genes. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Statistically significant associations were found for the APOE ɛ2 (OR, 0.51), GNB3 825T (OR, 1.38), MTHFR 677T (OR, 1.20), SLC6A4 44u2009bp Ins/Del S (OR, 1.11) alleles and the SLC6A3 40u2009bpVNTR 9/10 genotype (OR, 2.06). To date, there is statistically significant evidence for six MDD susceptibility genes (APOE, DRD4, GNB3, MTHFR, SLC6A3 and SLC6A4).

Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10−9, odds ratio = 1.23, 95% CI 1.150–1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10−11 (odds ratio = 1.18, 95% CI 1.127–1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 × 10−5, permuted threshold for genome-wide significance 7.7 × 10−5). To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

Influence of timing on CSF tests value for Creutzfeldt-Jakob disease diagnosis

AbstractBackgroundThenanalysis of markers in the cerebrospinalnfluid (CSF) is useful innthe diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD). However,nthe time at which the studynof these markers is most sensitivenremains controversal.ObjectiveTo assess the influence of time ofnsampling on the value of CSF testsnin the diagnosis of sCJD.MethodIn the framework of a multinationalnEuropean study, we studiednthe results of 14-3-3, S100b, neuronenspecific enolase (NSE) andntau protein in 833 CSF samplesnfrom sCJD patients at differentnstages of disease and in 66nsequentially repeated lumbarnpunctures (LP).Results14-3-3nand tau protein tended to increasenin sensitivity from onset (88%,n81%) to the advanced stage (91%,n90%). This was significant only innthe methionine-valine (MV) heterozygousngroup of patients atncodon 129. The absolute levels ofnS100b (p < 0.05), NSE and taunprotein increased in the last stagenof disease. High levels of taunprotein, NSE and S100b werenassociated with shorter survivalntimes (p < 0.01). Sixty-six sCJDnpatients underwent repeated LP.nThese sCJD patients were younger,nhad longer disease durations andnwere more frequently MV atncodon 129 (p < 0.001) than thenwhole group. 14-3-3 sensitivitynincreased from 64% to 82% in thensecond LP (p = 0.025) and 88%nsCJD patients had at least onenpositive result.ConclusionsSensitivitynand absolute levels of CJDnmarkers increased with diseasenprogression and were modulatednby the codon 129 genotype. Earlynnegative results should be inter-preted with caution, especially innyoung patients or those who arenMV at codon 129.

CSF analysis in patients with sporadic CJD and other transmissible spongiform encephalopathies

Patients with suspected Creutzfeldt–Jakob disease (CJD) often have routine cerebrospinal fluid (CSF) analysis performed to exclude treatable inflammatory conditions; however, little information is available about the range of results obtained for CSF tests in patients with sporadic CJD and other transmissible spongiform encephalopathies (TSE). Data from 450 patients with sporadic CJD and 47 patients with other TSEs were collected as part of an EC‐supported multinational study. Raised white cell counts of >5u2003cells/μl were found in three of 298 patients with sporadic CJD, with two cell counts of 7u2003cells/μl and one of 20u2003cells/μl. Total protein concentrations of >0.9u2003g/l were found in five of 438 patients with sporadic CJD, although none had a concentration of >1u2003g/l. CSF oligoclonal IgG was detected in eight of 182 sporadic CJD patients. Of the patients with other TSEs, six had elevated cell counts ranging from 6 to 14u2003cells/μl but none had total protein concentrations of >0.9u2003g/l and one patient had detectable oligoclonal IgG. None of the patients with sporadic CJD or other TSEs had abnormalities in all three tests.

Differential Roles of Angiotensinogen and Angiotensin Receptor type 1 Polymorphisms in Breast Cancer Risk

While angiotensinogen (AGT) seems to have anti proliferative properties, angiotensin II (ATII) is a potent growth factor and it mediates its actions through the angiotensin type 1 receptor (AGTR1). In the AGT gene, the M235T polymorphism has been associated with the variation in angiotensinogen levels and in the AGTR1 gene; the C573T variant is associated with different pathologies. We aimed to evaluate the relationship of these two variants and the risk of breast cancer. These polymorphisms were genotyped in 3787 women participating the Rotterdam Study. We performed a logistic regression and a disease free survival analysis by genotype. The logistic regression yielded an odds ratio of 1.4 (95% CI: 1.1–1.9) for the MM genotype carriers versus the T allele carriers. The breast cancer free survival by AGT genotype was significantly reduced in MM genotype carriers compared to non-carriers (hazard ratio (HR)xa0=xa01.5; 95% CI: 1.1–2.2). We did not find any association of the AGTR1 polymorphism and breast cancer risk or disease free survival. Our results suggest that AGT plays a role in breast cancer risk in postmenopausal women, whereas the role of AGTR1 needs further studying.

CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease

von Willebrand factor (VWF) levels in healthy individuals are influenced by variations in genetic loci other than the VWF gene, whose contribution to VWF levels in patients with von Willebrand disease (VWD) is largely unknown.

Association of an APOC3 promoter variant with type 2 diabetes risk and need for insulin treatment in lean persons

Aims/hypothesisAn APOC3 promoter haplotype has been previously associated with type 1 diabetes. In this population-based study, we investigated whether APOC3 polymorphisms increase type 2 diabetes risk and need for insulin treatment in lean participants.MethodsIn the Rotterdam Study, a population-based prospective cohort (nu2009=u20097,983), Cox and logistic regression models were used to analyse the associations and interactive effects of APOC3 promoter variants (−482Cu2009>u2009T, −455Tu2009>u2009C) and BMI on type 2 diabetes risk and insulin treatment. Analyses were followed by replication in an independent case–control sample (1,817 cases, 2,292 controls) and meta-analysis.ResultsIn lean participants, the −482T allele was associated with increased risk of prevalent and incident type 2 diabetes: OR −482CT 1.47 (95% CI 1.13–1.92), −482TT 1.40 (95% CI 0.83–2.35), pu2009=u20090.009 for trend; HR −482CT 1.35 (95% CI 0.96–1.89), −482TT 1.68 (95% CI 0.91–3.1), pu2009=u20090.03 for trend, respectively. These results were confirmed by replication. Meta-analysis was highly significant (−482T meta-analysis pu2009=u20091.1u2009×u200910-4). A borderline significant interaction was observed for insulin use among participants with type 2 diabetes (−482CT*BMI pu2009=u20090.06, −455TC*BMI pu2009=u20090.02).Conclusions/interpretationAt a population-based level, the influence of APOC3 promoter variants on type 2 diabetes risk varies with the level of adiposity. Lean carriers of the −482T allele had increased type 2 diabetes risk, while such an effect was not observed in overweight participants. Conversely, in overweight participants the −455C allele seemed protective against type 2 diabetes. The interaction of the variants with need for insulin treatment may indicate beta cell involvement in lean participants. Our findings suggest overlap in the genetic backgrounds of type 1 diabetes and type 2 diabetes in lean patients.

Linkage analysis of adult height in a large pedigree from a Dutch genetically isolated population

Despite extensive research of genetic determinants of human adult height, the genes identified up until now allow to predict only a small proportion of the trait’s variance. To identify new genes we analyzed 2,486 genotyped and phenotyped individuals in a large pedigree including 23,612 members in 18 generations. The pedigree was derived from a young genetically isolated Dutch population, where genetic heterogeneity is expected to be low and linkage disequilibrium has been shown to be increased. Complex segregation analysis confirmed high heritability of adult height, and suggested mixed model of height inheritance in this population. The estimates of the model parameters obtained from complex segregation analysis were used in parametric linkage analysis, which highlighted three genome-wide significant and additionally at least four suggestive loci involved in height. Significant peaks were located at the chromosomal regions 1p32 (LOD scorexa0=xa03.35), 2p16 (LOD scorexa0=xa03.29) and 16q24 (LOD scorexa0=xa03.94). For the latter region, a strong association signal (FDR qxa0<xa00.05) was obtained for 19 SNPs, 17 of them were located in the CDH13 (cadherin 13) gene of which one (rs1035569) explained 1.5% of the total height variance.

Short telomere length is associated with impaired cognitive performance in European ancestry cohorts

The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17u2009052; mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (β=0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (β=0.025; 95% CI: 0.002, 0.047; P=0.03), and faster STROOP (β=−0.053; 95% CI: −0.087, −0.018; P=0.003). Effects for DSST were stronger in APOE ɛ4 non-carriers (β=0.081; 95% CI: 0.045, 0.117; P=1.0 × 10−5), whereas carriers performed better in STROOP (β=−0.074; 95% CI: −0.140, −0.009; P=0.03). Causal associations were found for STROOP only (β=−0.598 per s.d.-increase of TL; 95% CI: −1.125, −0.072; P=0.026), with a larger effect in ɛ4-carriers (β=−0.699; 95% CI: −1.330, −0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE ɛ4-carriers might be at differential risk.

Candidate-gene association study searching for genetic factors involved in migraine chronification

Introduction Chronic migraine (CM) is at the severe end of the clinical migraine spectrum, but its genetic background is unknown. Our study searched for evidence that genetic factors are involved in the chronification process. Methods We initially selected 144 single-nucleotide polymorphisms (SNPs) from 48 candidate genes, which we tested for association in two stages: The first stage encompassed 262 CM patients, the second investigated 226 patients with high-frequency migraine (HFM). Subsequently, SNPs with p valuesu2009<u20090.05 were forwarded to the replication stage containing 531 patients with CM or HFM. Results Eight SNPs were significantly associated with CM and HFM in the two-stage phase. None survived replication in the third stage. Discussion We present the first comprehensive genetic association study for migraine chronification. There were no significant findings. Future studies may benefit from larger, genome-wide data sets or should use other genetic approaches to identify genetic factors involved in migraine chronification.