Effects of Alzheimer's disease-associated risk loci on cerebrospinal fluid biomarkers and disease progression: a polygenic risk score approach.

BACKGROUND: Several risk loci for Alzheimer's disease (AD) have been identified during recent years in large-scale genome-wide association studies. However, little is known about the mechanisms by which these loci influence AD pathogenesis. OBJECTIVE: To investigate the individual and combined risk effects of the newly identified AD loci. METHODS: Association of 12 AD risk loci with AD and AD-related cerebrospinal fluid (CSF) biomarkers was assessed. Furthermore, a polygenic risk score combining the effect sizes of the top 22 risk loci in AD was calculated for each individual among the clinical and neuropathological cohorts. Effects of individual risk loci and polygenic risk scores were assessed in relation to CSF biomarker levels as well as neurofibrillary pathology and different biochemical measures related to AD pathogenesis obtained from the temporal cortex. RESULTS: Polygenic risk scores associated with CSF amyloid-ß42 (Aß42) levels in the clinical cohort, and with soluble Aß42 levels and γ-secretase activity in the neuropathological cohort. The γ-secretase effect was independent of APOE. APOE-ε4 associated with CSF Aß42 (p < 0.001) levels. For the other risk loci, no significant associations with AD risk or CSF biomarkers were detected after multiple testing correction. CONCLUSIONS: AD risk loci polygenically contribute to Aß pathology in the CSF and temporal cortex, and this effect is potentially associated with increased γ-secretase activity.

Genetic loci associated with Alzheimer's disease and cerebrospinal fluid biomarkers in a Finnish case-control cohort.

OBJECTIVES: To understand the relation between risk genes for Alzheimer's disease (AD) and their influence on biomarkers for AD, we examined the association of AD in the Finnish cohort with single nucleotide polymorphisms (SNPs) from top AlzGene loci, genome-wide association studies (GWAS), and candidate gene studies; and tested the correlation between these SNPs and AD markers Aß(1-42), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). METHODS: We tested 25 SNPs for genetic association with clinical AD in our cohort comprised of 890 AD patients and 701-age matched healthy controls using logistic regression. For the correlational study with biomarkers, we tested 36 SNPs in a subset of 222 AD patients with available CSF using mixed models. Statistical analyses were adjusted for age, gender and APOE status. False discovery rate for multiple testing was applied. All participants were from academic hospital and research institutions in Finland. RESULTS: APOE-ε4, CLU rs11136000, and MS4A4A rs2304933 correlated with significantly decreased Aß(1-42) (corrected p<0.05). At an uncorrected p<0.05, PPP3R1 rs1868402 and MAPT rs2435211 were related with increased t-tau; while SORL1 rs73595277 and MAPT rs16940758, with increased p-tau. Only TOMM40 rs2075650 showed association with clinical AD after adjusting for APOE-ε4 (p = 0.007), but not after multiple test correction (p>0.05). CONCLUSIONS: We provide evidence that APOE-ε4, CLU and MS4A4A, which have been identified in GWAS to be associated with AD, also significantly reduced CSF Aß1-42 in AD. None of the other AlzGene and GWAS loci showed significant effects on CSF tau. The effects of other SNPs on CSF biomarkers and clinical AD diagnosis did not reach statistical significance. Our findings suggest that APOE-ε4, CLU and MS4A4A influence both AD risk and CSF Aß1-42.

Sexually dimorphic effect of the Val66Met polymorphism of BDNF on susceptibility to Alzheimer's disease: New data and meta-analysis.

Conflicting results have been reported as to whether genetic variations (Val66Met and C270T) of the brain-derived neurotrophic factor gene (BDNF) confer susceptibility to Alzheimer's disease (AD). We genotyped these polymorphisms in a Japanese sample of 657 patients with AD and 525 controls, and obtained weak evidence of association for Val66Met (P = 0.063), but not for C270T. After stratification by sex, we found a significant allelic association between Val66Met and AD in women (P = 0.017), but not in men. To confirm these observations, we collected genotyping data for each sex from 16 research centers worldwide (4,711 patients and 4,537 controls in total). The meta-analysis revealed that there was a clear sex difference in the allelic association; the Met66 allele confers susceptibility to AD in women (odds ratio = 1.14, 95% CI 1.05-1.24, P = 0.002), but not in men. Our results provide evidence that the Met66 allele of BDNF has a sexually dimorphic effect on susceptibility to AD.

RGS4 polymorphism and response to electroconvulsive therapy in major depressive disorder.

We studied the association between RGS4 (rs951436) polymorphism and treatment response in electroconvulsive therapy (ECT) as well as risk of treatment-resistant depression. The study sample consisted of 119 patients with major depressive disorder (MDD) and 384 healthy control subjects. RGS4 polymorphism was not associated with treatment response in ECT or risk of MDD. According to the present data, the impact of RGS4 genotype is not decisive in major depressive disorder. The results provide preliminary data on the impact of RGS4 polymorphism in treatment response in ECT.

Interleukin-1 beta gene polymorphism and its interactions with neuregulin-1 gene polymorphism are associated with schizophrenia.

Interleukin-1beta (IL-1beta) and neuregulin-1 (NRG-1) have an important role in development of the central nervous system. Several recent studies suggest that their genetic polymorphisms are associated with schizophrenia. We studied the effects of the IL-1beta gene (IL-1B) -511 and NRG-1 SNP8NRG221533 polymorphisms and their interactions on the risk and age of onset of schizophrenia in 113 Finnish schizophrenic patients and 393 healthy controls. The allele and genotype frequencies of IL-1B and NRG-1 did not differ between schizophrenic patients and healthy controls, but the risk of schizophrenia was more than 10 times higher (odds ratio 10.20, 95% CI 2.53-41.09, p = 0.001) among subjects with the IL-1B 2.2, NRG-1 CC genotypes compared to subjects with the IL-1B 2.2, NRG-1 T-allele carriage. There was also a trend for an association between the interaction between IL-1B and NRG-1 polymorphisms and the age at onset of schizophrenia (chi(2) = 2.80; df = 1; p = 0.09, log rank test). IL-1B-511 allele 1 homozygotes had a significantly higher age of onset than allele 2 carriers (mean age of onset 25.9 +/- 7.7 and 22.7 +/- 5.4 years, t-test: t = 2.46; p = 0.032). Our results suggest that there is an interaction between the IL-1B and NRG-1 genes in schizophrenia. In addition, the IL-1B-511 polymorphism seems to be associated with the age at onset of schizophrenia.

Catechol-O-methyltransferase val108/158met genotype and response to antipsychotic medication in schizophrenia.

Catechol-O-methyltransferase (COMT) gene has been investigated as a possible candidate gene in schizophrenia. The most studied polymorphism has been the functional val108/158met polymorphism of this COMT gene. There is also some evidence that this polymorphism could be related to drug response to antipsychotics in schizophrenia. COMT enzyme inactivates dopamine and noradrenaline. Based mainly on the original dopamine theory of schizophrenia, our primary hypothesis was that the maintenance dose of antipsychotics would be higher in patients with the low activity COMT genotype. In this study we evaluated the current daily dosage of antipsychotics in 180 patients with schizophrenia in connection with the COMT genotype. We could not demonstrate any clearly significant effect of this particular COMT genotype in relation to the daily maintenance dosages of antipsychotics in patients with schizophrenia.

Association between the C957T polymorphism of the dopamine D2 receptor gene and schizophrenia.

The aim of this study was to investigate the relationship between the functional C957T single-nucleotide polymorphism of the dopamine D2 receptor (DRD2) gene and the risk for schizophrenia. We therefore conducted a case-control association study of 188 Finnish schizophrenia patients meeting the DSM-IV criteria and 384 healthy controls. The 5' nuclease assay (TaqMan) was used to determine genotypes. A greater proportion of patients with schizophrenia than healthy controls were C-allele carriers (odds ratio 1.5, 95% confidence interval (CI) 1.0-2.3, P=0.05). Our results are in agreement with an earlier association study suggesting that the C957T C-allele plays a role in the genetic vulnerability for schizophrenia and support the involvement of the DRD2 gene in schizophrenia pathogenesis.

No association between the brain-derived neurotrophic factor 196 G>A or 270 C>T polymorphisms and Alzheimer's or Parkinson's disease.

The brain-derived neurotrophic factor (BDNF) promotes survival, differentiation and maintenance of neurons in the central nervous system. BDNF 196 G>A and 270 C>T polymorphisms have previously been associated with Alzheimer's disease (AD) and with Parkinson's disease (PD). To study the role of BDNF 196 G>A and 270 C>T polymorphisms in Finnish AD and PD patients we genotyped BDNF 196 G>A and 270 C>T polymorphisms in 97 sporadic AD patients, 52 PD patients and 101 control subjects with polymerase chain reaction. No associations were found between the genotypes studied and AD or PD in Finnish patients. Moreover, no interaction between either BDNF polymorphism and the epsilon 4 allele of apolipoprotein E was found. In conclusion, it seems that the BDNF gene does not contribute significantly to the risk of AD or PD in Finnish patients.

High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial.

BACKGROUND: Myopathy, probably caused by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition in skeletal muscle, rarely occurs in patients taking statins. This study was designed to assess the effect of high-dose statin treatment on cholesterol and ubiquinone metabolism and mitochondrial function in human skeletal muscle. METHODS: Forty-eight patients with hypercholesterolemia (33 men and 15 women) were randomly assigned to receive 80 mg/d of simvastatin (n = 16), 40 mg/d of atorvastatin (n = 16), or placebo (n = 16) for 8 weeks. Plasma samples and muscle biopsy specimens were obtained at baseline and at the end of the follow-up. RESULTS: The ratio of plasma lathosterol to cholesterol, a marker of endogenous cholesterol synthesis, decreased significantly by 66% in both statin groups. Muscle campesterol concentrations increased from 21.1 +/- 7.1 nmol/g to 41.2 +/- 27.0 nmol/g in the simvastatin group and from 22.6 +/- 8.6 nmol/g to 40.0 +/- 18.7 nmol/g in the atorvastatin group (P = .005, repeated-measurements ANOVA). The muscle ubiquinone concentration was reduced significantly from 39.7 +/- 13.6 nmol/g to 26.4 +/- 7.9 nmol/g (P = .031, repeated-measurements ANOVA) in the simvastatin group, but no reduction was observed in the atorvastatin or placebo group. Respiratory chain enzyme activities were assessed in 6 patients taking simvastatin with markedly reduced muscle ubiquinone and in matched subjects selected from the atorvastatin (n = 6) and placebo (n = 6) groups. Respiratory chain enzyme and citrate synthase activities were reduced in the patients taking simvastatin. CONCLUSIONS: High-dose statin treatment leads to changes in the skeletal muscle sterol metabolism. Furthermore, aggressive statin treatment may affect mitochondrial volume.

Tumor necrosis factor-alpha --G308A polymorphism in schizophrenia in a Finnish population.

Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine with functions in nerve cell growth, differentiation, and apoptosis. There are several studies showing that a TNF-alpha--G308A promoter polymorphism, which possibly affects TNF-alpha transcription, is associated with schizophrenia, although negative results also exist. Our aim was to investigate the relationship between the TNF-alpha --G308A promoter polymorphism, the risk of schizophrenia, and the age of onset of schizophrenia, and the TNF-alpha -G308A polymorphism was therefore studied in 149 southern Finnish patients with a DSM-IV diagnosis of schizophrenia and in 393 healthy controls. The allele and genotype frequencies did not differ significantly between the patient and control groups (P=0.10 and 0.12, respectively), but the frequency of G/G homozygotes was statistically significantly higher in male patients than in male controls (chi(2)=5.03, d.f.=1, P=0.025) with an odds ratio of 2.00 (95% confidence interval: 1.08--3.70). No such difference was seen in female patients (P=0.79) or in the whole study group (P=0.064). The age of onset of schizophrenia did not differ significantly between the different TNF-alpha genotypes (ANOVA: F=0.45, P=0.64). In conclusion, we did not find a clear association between the TNF-alpha --G308A polymorphism and schizophrenia in the whole study group. However, TNF-alpha --G308A G/G homozygosity was modestly associated with schizophrenia in male patients.

Matrix metalloproteinase3 and 9 gene promoter polymorphisms: joint action of two loci as a risk factor for coronary artery complicated plaques.

OBJECTIVE: Matrix metalloproteinases 3 and 9 (MMP3 and MMP9) are present in atherosclerotic plaques and co-operate in the degradation of the fibrous cap of the atheroma, leading to fissuring and ultimately to acute coronary thrombosis. The functional genetic polymorphisms in the promoters of MMP3 and MMP9, which lead to low- and high-transcription activity genotypes, have been shown to be associated with myocardial infarction and angiographically measured atherosclerosis individually, whereas their effects in combination are not yet known. In order to assess the two disease loci simultaneously, we investigated the association of combined low and high promoter activity genotypes with different types of coronary lesions in an autopsy cohort of 300 Caucasian males aged 33-69 years (Helsinki Sudden Death Study). METHODS: Genotyping at these loci was performed by PCR, restriction enzyme digestion and minisequencing, and areas of the coronary wall covered with atherosclerotic lesions were measured using computer-assisted morphometry. RESULTS: In analysis of covariance (ANCOVA) with age, body mass index, hypertension, diabetes, smoking and alcohol consumption as covariates, a significant interaction between the MMP3 and MMP9 genotypes was observed on area of complicated lesions (P=0.012). Men with high promoter activity genotypes for both loci had, on average, more than two times larger area of complicated lesions (250%) compared with those men who had low promoter activity genotypes (P=0.008), but these loci showed no association with myocardial infarction. CONCLUSIONS: The joint action of two susceptibility loci, rather than single MMP genes alone, and the particular combination of MMP3 and MMP9 genotypes present at these loci may contribute to heterogeneity in the presentation of atherosclerosis.

The apolipoprotein E polymorphism is not associated with response to electroconvulsive therapy in major depressive disorder.

The apolipoprotein E (APOE) polymorphism is associated with neurodegenerative diseases. Its role regarding psychiatric disorders is controversial. It has been suggested to affect antidepressant treatment response and response to electroconvulsive therapy (ECT). In the present study, the association between APOE polymorphism and response to ECT in 119 patients with major depressive disorder was investigated. Moreover, a relation between APOE polymorphism and the age of onset of depression as well as the cognitive outcome of ECT was studied. In the whole population, no association was found between APOE polymorphism and response to ECT. However, in nonpsychotic patients, the epsilon2 allele tended to be more frequent in responders than nonresponders. Earlier onset of depression was observed in the patients with epsilon4 allele in late-life depression. There was no association between the APOE genotype and the cognitive change caused by ECT in the population as a whole. In women, however, epsilon2 allele may play a protective and epsilon4 allele a deleterious role in cognition during ECT.

Interaction of tumor necrosis alpha - G308A and epidermal growth factor gene polymorphisms in early-onset schizophrenia.

The study population comprised 94 Finnish patients with DSM-IV diagnosis of schizophrenia. The patients were placed into two subgroups according to medication response to conventional neuroleptics. The aim of the study was to examine the frequency of tumor necrosis factor -308 (G > A) polymorphism in these patients and their 98 control subjects who were age- and gender-matched blood donors. Associations between TNFalpha -308 polymorphism alone and between the interaction of TNFalpha and epidermal growth factor gene polymorphisms, and medication response and age at onset of schizophrenia were also studied. The frequencies of TNFalpha A-allele were 11.7 % in patients and 12.8% in controls. The difference was not significant (p = 0.75). TNFalpha -308 polymorphism was not associated with medication response. However, patients with EGF AA and TNFalpha AG/AA genotype had a lower age at onset of schizophrenia compared with the rest of the patients not having this combination (20.0 years, 3.3 vs. 30.2 years, 10.1 mean + SD; p < 0.001). The results support earlier findings according to which TNFalpha polymorphism is not associated with the incidence of schizophrenia. On the other hand, the role of cytokines in schizophrenia may involve genetic interactions predisposing early onset of illness.

Neuregulin genotype and medication response in Finnish patients with schizophrenia.

Neuregulin 1 is involved both in neurodevelopment and neurotransmitter mechanisms in the brain. There is evidence of an association between neuregulin 1 genotype and schizophrenia. We compared neuregulin 1 genotypes in patients with schizophrenia (n=94) and control subjects (n=395) of Finnish origin by using one SNP (SNP8NRG221533) as a genetic marker. We also analyzed NRG1 genotype with regard to age at onset and between responders and non-responders to conventional antipsychotics. The NRG1 genotype or allele frequencies showed similar distributions between patient and control groups. Age at onset was not associated with NRG1 genotype. The TT genotype was overrepresented in the non-responders group compared with the responders (p=0.013). Further studies are needed to ascertain the significance of neuregulin genotype in medication response to schizophrenia.

Interaction between matrix metalloproteinase 3 and the epsilon4 allele of apolipoprotein E increases the risk of Alzheimer's disease in Finns.

Polymorphisms affecting the expression of matrix metalloproteinases (MMPs), i.e. proteolytic enzymes that degrade intercellular material, have been found at position -1607 (1G/2G) in MMP1 and at -1171 (5A/6A) in MMP3. Interestingly, elevated levels of MMP1 and MMP3 have been observed in the brains of Alzheimer's disease (AD) patients and those of tissue inhibitors of MMPs in the cerebrospinal fluid of AD and Parkinson's disease (PD) patients, suggesting a role for MMPs in these disorders. The aim was to investigate a possible association between the afore-mentioned MMP1 and MMP3 polymorphisms and the risk of developing AD or PD. The polymorphisms were genotyped in 97 AD, 52 PD and 101 control patients. We found an interaction between MMP3*5A and APOE 4 alleles (P < 0.0001) which increases the risk of AD (OR: 23.7, 95% CI: 5.8-144.9, P < 0.0001) compared to those who possess neither MMP3*5A nor APOE 4. In conclusion, our finding suggests that the MMP3 gene, especially together with APOE 4, may contribute to the development of AD.

Apolipoprotein E polymorphism is associated with age of onset in schizophrenia.

The aims of the study were to investigate the relationship between Apolipoprotein E (APOE) polymorphism, risk of schizophrenia, treatment response to conventional anti-psychotics, and age of onset in schizophrenia. The sample comprised 94 Finnish patients with a DSM-IV diagnosis of schizophrenia. Forty-three of the patients were good responders to conventional anti-psychotics and 51 were classified as non-responders. The control group consisted of 98 healthy blood donors. The APOE allele frequencies (epsilon 2, epsilon 3, and epsilon 4) were 4.8, 72.3, and 22.9% in patients and 7.1, 75.0, and 17.9 in controls. None of the differences between groups were statistically significant. No association between treatment response and APOE genotype was found. Patients with APOE epsilon 4/epsilon 4 genotype had a markedly lower age of onset compared with rest of the sample (p=0.0015), which remained significant when controlling for gender (p=0.02). There was an increasing linear trend between the number of epsilon 3 alleles (0, 1, or 2) and age of onset in schizophrenia (p=0.08). An inverse trend was found between the number of epsilon 4 alleles and age of onset (p=0.07). No relationship between APOE polymorphism and risk for schizophrenia was found. APOE epsilon 4/epsilon 4 genotype may be associated with early onset schizophrenia. APOE epsilon 3 allele may function protectively in later onset in this disease.

Association of EGF polymorphism with schizophrenia in Finnish men.

Some recent data suggest that epidermal growth factor (EGF) protein levels are altered in the brain of schizophrenic patients. In addition, a novel polymorphism of the EGF gene is associated with enhanced production of EGF in vitro. We conducted a retrospective study to explore the impact of EGF polymorphism on factors associated with schizophrenia. The sample consisted of 94 patients with schizophrenia who had either responded to treatment with conventional neuroleptics or who were considered non-responders. The control sample consisted of 98 blood donors. In our sample, the G allele was associated with schizophrenia in male patients (OR = 3.594 (95% CI 1.347-9.591), p = 0.008). The G allele was also associated with a later age at onset in male patients with schizophrenia. However, no association was found between treatment response and EGF polymorphism.

Interaction between NOTCH4 and catechol-O-methyltransferase genotypes in schizophrenia patients with poor response to typical neuroleptics.

OBJECTIVE: In this study we attempted to show that the interaction between NOTCH4 and catechol-O-methyltransferase (COMT) polymorphism predicts the response to typical neuroleptics in schizophrenia. Our sample consisted of 94 Finnish patients with DSM-IV schizophrenia and 98 controls. METHODS: Several studies have connected COMT and NOTCH4 genes to schizophrenia. We have previously shown that COMT polymorphism is significantly associated with treatment response in schizophrenia. NOTCH4 SNP2 polymorphism has been associated with age of onset in schizophrenia, but there is also a trend that this polymorphism may predict response to typical neuroleptics. In the present sample, there is a strong gene-gene interaction between these genes (P = 0.003) and they have additive effect in treatment response. RESULTS: Patients carrying both NOTCH4 C/C genotype and COMT low/low genotype, had more than ten times higher risk of being a non-responder than responder to treatment with typical neuroleptics [OR = 10.25 (95% CI 2.21-47.53), P < 0.001]. This combination of genotypes is also more common in patients considered non-responders than in controls [OR = 3.00 (95% CI 1.33-6.76), P = 0.007]. CONCLUSION: Our results suggest that an interaction between COMT and NOTCH4 genotypes may predict the treatment response to typical neuroleptics in patients with schizophrenia.

Catechol-O-methyltransferase and monoamine oxidase A genotypes and drug response to conventional neuroleptics in schizophrenia.

Biogenic amine synthesis and degradation are involved in the pathogenesis of schizophrenia. Catechol-O-methyltransferase and monoamine oxidase enzymes are important agents in the metabolic inactivation of these neurotransmitters (ie, dopamine, serotonin, and norepinephrine). Functional polymorphism in the catechol-O-methyltransferase and monoamine oxidase A genes causes variation in enzyme activities. We investigated the relationship of catechol-O-methyltransferase Val158Met and monoamine oxidase A promoter repeat polymorphism with response to conventional neuroleptic treatment in schizophrenia.Ninety-four schizophrenic patients formed 2 different study populations. The responders had experienced a fair and steady response to conventional neuroleptics. The nonresponders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age-matched and gender-matched blood donors. Genotyping of the catechol-O-methyltransferase and monoamine oxidase A genes was performed by polymerase chain reaction.Forty-three percent of the nonresponders had a low activity catechol-O-methyltransferase genotype compared with 16% of the responders (P = 0.009). Monoamine oxidase A genotype alone did not differ significantly between the groups. Moreover, the risk of having both low-activity catechol-O-methyltransferase and monoamine oxidase A genotypes was over 6 times more common (odds ratio = 6.16, P = 0.03) in the nonresponders compared with responders. The whole population of patients with schizophrenia did not differ from the controls.The low-activity catechol-O-methyltransferase genotype may be associated with unsatisfactory drug response to conventional neuroleptics or alternatively be involved in a subset of schizophrenics. The role of monoamine oxidase A genotype seems to be additive in this respect.

Dopamine receptor D2 -141C Insertion/Deletion polymorphism in a Finnish population with schizophrenia.

We examined the occurrence of the -141C Ins/Del polymorphism in 93 Finnish patients with schizophrenia. In comparison with previous studies with Japanese and Caucasian populations, the incidence of this polymorphism was unexpectedly low. The findings suggest that the frequency of the -141C Ins/Del polymorphism is lower in Northern Europe compared to other Caucasian and Japanese populations.