ABO Blood Groups, RhD Factor and Their Association with Subclinical Atherosclerosis Assessed by Carotid Ultrasonography.

Background: The ABO blood group system has previously been associated with cardiovascular disease (CVD), where non-O blood group individuals have shown an increased risk. Studies assessing early atherosclerotic disease while also including RhD are few. We aimed to determine whether the ABO and RhD blood groups are associated with subclinical atherosclerosis in a healthy population. Methods: We included 3532 participants from the VIPVIZA trial with available carotid ultrasonography results to assess subclinical disease. Information about blood groups was obtained from the SCANDAT-3 database, where 85% of VIPVIZA participants were registered. Results: RhD- individuals aged 40 years showed increased carotid intima-media thickness (B 1.09 CI 95% 1.03; 1.14) compared to RhD+ individuals. For ABO, there were no differences in ultrasonography results when assessing the whole study population. However, 60-year-old individuals with heredity for CVD and a non-O blood group had decreased odds for carotid plaques (OR 0.54 CI 95% 0.33; 0.88). Conclusions: RhD blood group is associated with subclinical atherosclerosis in younger individuals, indicating a role as a mediator in the atherosclerotic process. In addition, a non-O blood group was associated with decreased subclinical atherosclerosis in individuals aged 60 and with heredity (corresponding to the group with the highest atherosclerotic burden).

The effect of tourniquet use on postoperative opioid consumption after ankle fracture surgery - a retrospective cohort study.

OBJECTIVES: A pneumatic tourniquet is often used during ankle fracture surgery to reduce bleeding and enhance the visibility of the surgical field. Tourniquet use causes both mechanical and ischemic pain. The main purpose of this study was to evaluate the effect of tourniquet time on postoperative opioid consumption after ankle fracture surgery. METHODS: We retrospectively reviewed the files of 586 adult patients with surgically treated ankle fractures during the years 2014-2016. We evaluated post hoc the effect of tourniquet time on postoperative opioid consumption during the first 24 h after surgery. The patients were divided into quartiles by the tourniquet time (4-43 min; 44-58 min; 59-82 min; and ≥83 min). Multivariable linear regression analysis was used to evaluate the results. RESULTS: Tourniquets were used in 486 patients. The use of a tourniquet was associated with an increase in the total postoperative opioid consumption by 5.1 mg (95 % CI 1.6-8.5; p=0.004) during the first 24 postoperative hours. The tourniquet time over 83 min was associated with an increase in the mean postoperative oxycodone consumption by 5.4 mg (95 % CI 1.2 to 9.7; p=0.012) compared to patients with tourniquet time of 4-43 min. CONCLUSIONS: The use of a tourniquet and prolonged tourniquet time were associated with higher postoperative opioid consumption during the 24 h postoperative follow-up after surgical ankle fracture fixation. The need for ethical approval and informed consent was waived by the Institutional Review Board of Northern Ostrobothnia Health District because of the retrospective nature of the study.

Associations between emotional support and cardiovascular risk factors and subclinical atherosclerosis in middle-age.

OBJECTIVE: To test the hypothesis of low emotional support being associated with lifestyle and biomedical cardiovascular disease (CVD) risk factors, estimated risk of CVD morbidity and mortality, and subclinical atherosclerosis in middle-aged healthy adults. METHODS AND MEASURES: Cross-sectional data were obtained from participants aged 40-60 years who had one or more conventional CVD risk factor. They underwent assessment based on questionnaires, clinical examination, blood sampling, and carotid ultrasound of plaque formation and carotid intima-media wall thickness (cIMT). Based on the Interview Schedule for Social Interaction, the participants were categorised as either low in emotional support (n = 884) or as a referent (n = 2570). Logistic regression analyses were conducted to study the associations. RESULTS: Logistic regression analyses showed that low emotional support was significantly associated with smoking, alcohol consumption and physical inactivity (OR = 1.53 - 1.94), estimated risk of CVD morbidity and mortality (OR = 1.56 - 1.68), and plaque formation (OR = 1.39). No significant associations were found regarding biomedical CVD risk factors or cIMT. CONCLUSION: The findings suggest that low social support is associated with lifestyle CVD risk factors, estimated risk of CVD morbidity and mortality, and subclinical atherosclerosis in middle-aged healthy adults, encouraging causal evaluation with longitudinal data investigating an impact of emotional support on mechanisms underlying CVD.

Changes in fasting plasma glucose and subclinical atherosclerosis: A cohort study from VIPVIZA trial.

BACKGROUND AND AIMS: Studies on the influence of fasting plasma glucose (FPG) on the development of carotid plaque (CP) and intima media thickness (CIMT) mainly focused on single FPG measures. We investigated whether changes in FPG (ΔFPG) are associated with incident CP and CIMT change (ΔCIMT) over time. METHODS: Analyses were based on information from 1896 participants from the VIPVIZA trial (Visualization of asymptomatic atherosclerotic disease for optimum cardiovascular prevention), with baseline and 3-year follow-up data on FPG, ultrasonographic CP (none or ≥1 lesion/s) and CIMT assessments. We studied the association between baseline FPG (prior to intervention) or 3-year ΔFPG (mmol/L) and incident CP (logistic regression) or ΔCIMT (linear regression). Analyses were adjusted for multiple potential confounders. RESULTS: 1896 and 873 individuals, respectively, were included in the analysis on incident CP and ΔCIMT. Participants were 60 years old at baseline and 61% and 54% were females, in the CP and CIMT analyses, respectively. Every mmol/L increase in FPG was associated with an increased odds of incident CP (odds ratio: 1.42, 95% confidence interval [CI]: 1.17, 1.73), but there was no association with ΔCIMT (mean difference: 0.002 mm, 95% CI: -0.003, 0.008) after 3 years. Baseline FPG was not associated with incident CP nor ΔCIMT progression. CONCLUSIONS: In middle-aged individuals with low to moderate risk for cardiovascular diseases, 3-year ΔFPG was positively associated with the risk of incident CP, but not with ΔCIMT. Single measures of FPG may not be sufficient in estimating cardiovascular risk among individuals with low to moderate risk.

Multi-view carotid ultrasound is stronger associated with cardiovascular risk factors than presence of plaque or single carotid intima media thickness measurements in subclinical atherosclerosis.

We aimed to explore the prevalence of atherosclerosis by using multi-view ultrasound examination of the carotid arteries and its association with clinical risk factors in a middle-aged population at low to intermediate risk of cardiovascular disease (CVD). Carotid vascular ultrasound was performed in 3532 participants in the VIPVIZA trial. Mean and maximal carotid intima media thickness (cIMT) at prespecified angles and plaque presence were examined on the left and right side. Associations between CVD risk factors and ultrasound variables were quantified by partial least squares (PLS) regression. A combined ultrasound variable was computed using weights of the first PLS component. Associations between CVD risk factors and the combined multi-view ultrasound variable, single cIMT and plaque measurements, respectively, were determined using linear regression modelling. The participants' mean age was 55.7 years and 52.9% were women. Plaque prevalence was 51.1% in men and 39.0% in women. cIMT was higher in men than in women and in the left compared with the right carotid artery. The strongest association of CVD risk factors was observed with the combined multi-view ultrasound variable (R2 = 24%), compared with single cIMT variables (R2 = 14-18%) and plaque presence (R2 = 15%). The pattern was similar in both sexes. The association with CVD risk factors and the combined ultrasound variable was stronger in 40-year olds (R2 = 22%) compared with 50- or 60-year olds (R = 12%). CVD risk factors are stronger associated with a combined ultrasound variable than plaque presence or single cIMT measures suggesting that carotid multi-view ultrasonography better captures the focality of early atherosclerosis.Clinical Trial Registration: ClinicalTrials.gov, number NCT01849575. May 8, 2013.

Carotid wall echogenicity at baseline associates with accelerated vascular aging in a middle-aged population.

Ultrasonic echolucent carotid intima-media (IM) complex and accelerated progression of carotid intima mediathickness (cIMT) have both separately been shown to predict future cardiovascular events. The aim of this studywas to evaluate if the echogenicity of the IM-complex is associated with the 3-year progression of cIMT. B-modeultrasound images captured at baseline and 3-year follow-up in the 'Visualization of asymptomatic atherosclerotic disease for optimum cardiovascular prevention' (VIPVIZA) trial were included (n: 3154). The bilateral mean cIMT and IM-echogenicity by greyscale median (GSM) were measured in the common carotid artery. Associations between IM-GSM at baseline and the 3-year cIMT progression were investigated using linear regression models for the whole population and stratified by sex, age and VIPVIZA study group (intervention versus control). In addition, adjusted analyses for confounding factors were performed. Unadjusted analysis showed that decreased IM-GSM at baseline was associated with increased progression of cIMT (p < 0.001). Stratified by age, the association was significant among 40 (p < 0.001) and 60 years old (p < 0.001). The association was statistically significant in both sexes and on comparison of VIPVIZA study subgroups. Adjustments for confounding factors did not alter the estimated relationship between IM-GSM and cIMT progression. Echolucent carotid intima media at baseline associates with increased 3-year cIMT progression among an asymptomatic, middle-aged population. Echogenicity of the intima media may identify individuals at risk for accelerated vascular aging.

Reduced progression of carotid intima media thickness by personalised pictorial presentation of subclinical atherosclerosis in VIPVIZA-A randomised controlled trial.

OBJECTIVES: Reduced progression of atherosclerosis can decrease the risk of cardiovascular disease (CVD). This study aimed at evaluating the effect of a pictorial intervention showing atherosclerotic severity on the progression of carotid atherosclerosis. METHODS: A prospective randomised open-label blinded end-point trial with participants aged 40-60 years enroled from a routine CVD prevention programme. The intervention group (n: 1575) and their treating physicians received an image based presentation of subclinical atherosclerotic severity measured by carotid ultrasound. The control group (n: 1579) did not receive any information about ultrasound results. Carotid ultrasound at baseline and at 3-year follow-up contained plaque detection and measurements of carotid intima media thickness (cIMT). The left, right and bilateral-mean-cIMT, plaque prevalence and total plaque area (TPA) at 3-year follow-up were compared between groups. Significance level was set to p = 0.01 to adjust for multiple comparisons. RESULTS: The intervention group revealed reduced cIMT progression in the left-mean-cIMT of -0.011 mm (p = 0.001) compared with the control group. The intervention effect on cIMT progression was most prominent in individuals with increased cIMT and plaque prevalence at baseline (-0.021 mm, p = 0.005). There were no differences in progression between groups for the right-and bilateral-mean-cIMT (-0.005 mm, p = 0.223 and -0.005 mm, p = 0.036, respectively), nor any differences between groups for plaque prevalence or TPA (odds ratio 0.88, p = 0.09 and 0.89, p = 0.21, respectively). CONCLUSION: Pictorial presentation of subclinical atherosclerotic severity sent to both the individual and their treating physician resulted in significantly reduced left cIMT progression. Pictorial presentation has the potential to increase adherence in CVD prevention.

Interframe Echo Intensity Variation of Subregions and Whole Plaque in Two-Dimensional Carotid Ultrasonography: Simulations and In Vivo Observations.

OBJECTIVES: The risk of cardiovascular disease is associated with the echo intensity of carotid plaques in ultrasound images and their cardiac cycle-induced intensity variations. In this study, we aimed to 1) explore the underlying origin of echo intensity variations by using simulations and 2) evaluate the association between the two-dimensional (2D) spatial distribution of these echo intensity variations and plaque vulnerability. METHODS: First, we analyzed how out-of-plane motion and compression of simulated scattering spheres of different sizes affect the ultrasound echo intensity. Next, we propose a method to analyze the features of the 2D spatial distribution of interframe plaque echo intensity in carotid ultrasound image sequences and explore their associations with plaque vulnerability in experimental data. RESULTS: The simulations showed that the magnitude of echo intensity changes was similar for both the out-of-plane motion and compression, but for scattering objects smaller than 1 mm radius, the out-of-plane motion dominated. In experimental data, maps of the 2D spatial distribution of the echo intensity variations had a low correlation with standard B-mode echo intensity distribution, indicating complementary information on plaque tissue composition. In addition, we found the existence of ∼1 mm diameter subregions with pronounced echo intensity variations associated with plaque vulnerability. CONCLUSIONS: The results indicate that out-of-plane motion contributes to intra-plaque regions of high echo intensity variation. The 2D echo intensity variation maps may provide complementary information for assessing plaque composition and vulnerability. Further studies are needed to verify this method's role in identifying vulnerable plaques and predicting cardiovascular disease risk.

The beneficial effect over 3 years by pictorial information to patients and their physician about subclinical atherosclerosis and cardiovascular risk: Results from the VIPVIZA randomized clinical trial.

OBJECTIVE: Non-adherence to guidelines and preventive measures is a major challenge, particularly so to obtain long-term adherence to lifestyle changes and recommended medication. The objective was to investigate if pictorial information regarding subclinical carotid atherosclerosis provided to individuals and physicians gave sustained effects on cardiovascular risk beyond the previously reported effect after 1 year and up to 3 years. METHODS: A Prospective Randomized Open Blinded End-point (PROBE) trial. Within a CVD prevention program in Västerbotten County, Sweden, 3532 healthy individuals aged 40, 50 or 60 years were enrolled and 1:1 randomized to intervention (n = 1749; pictorial information with additional prevention materials to participants and physicians) or control group (n = 1783; no pictorial information to participants and physicians). Preventive measures were managed within primary care. Participants were investigated at baseline during 2013-2016 and at follow-up after 1 and 3 years. RESULTS: A beneficial effect on cardiovascular risk was observed at 3-year follow-up; Framingham Risk Score (FRS) was 13.38 for the intervention group and 14.08 for the control group (p = 0.047) and SCORE was 1.69 vs. 1.82 (p = 0.022). The effect observed at 1-year was sustained over 3 years after adjustment for sex and education and more pronounced among participants with a severe atherosclerotic picture at baseline. CONCLUSIONS: This study provides evidence of sustained beneficial effects on the adherence to prevention guidelines over 3 years of pictorial information about subclinical carotid atherosclerosis, resulting in lower cardiovascular risk regardless of sex and educational level. Direct visualization of the underlying still subclinical atherosclerotic disease, rather than just indirect information about risk factors and statistical risk of future myocardial infarction, stroke and death, is one way to tackle the problem of non-adherence to prevention of cardiovascular diseases.

Difference in postoperative opioid consumption after spinal versus general anaesthesia for ankle fracture surgery-A retrospective cohort study.

BACKGROUND: Surgical treatment of ankle fracture is associated with significant pain and high postoperative opioid consumption. The anaesthesia method may affect early postoperative pain. The main objective of the study was to compare postoperative opioid consumption after ankle-fracture surgery between patients treated with spinal anaesthesia and general anaesthesia. METHODS: We reviewed retrospectively the files of 586 adult patients with surgically treated ankle fracture in the years 2014 through 2016. The primary outcome was opioid consumption during the first 48 postoperative hours. Secondary outcomes were maximal pain scores, postoperative nausea and vomiting, the length of stay in the post-anaesthesia care unit, and opioid use in different time periods up to 48 h postoperatively. Propensity score matching was used to mitigate confounding variables. RESULTS: Total opioid consumption 48 h postoperatively was significantly lower after spinal anaesthesia (propensity score-matched population: effect size -13.7 milligrams; 95% CI -18.8 to -8.5; P < .001). The highest pain score on the numerical rating scale in the post-anaesthesia care unit was significantly higher after general anaesthesia (propensity score-matched population: effect size 3.7 points; 95% CI 3.2-4.2; P < .001). A total of 60 patients had postoperative nausea and vomiting in the post-anaesthesia care unit, 53 (88.3%) of whom had general anaesthesia (P = .001). CONCLUSIONS: Patients with surgically treated ankle fracture whose operation was performed under general anaesthesia used significantly more opioids in the first 48 h postoperatively, predominantly in the post-anaesthesia care unit, compared with patients given spinal anaesthesia.

Ultrasound risk marker variability in symptomatic carotid plaque: impact on risk reclassification and association with temporal variation pattern.

PURPOSE: Ultrasound examinations of atherosclerotic carotid plaques can be used to calculate risk markers associated with plaque vulnerability. Recent studies demonstrate significant inter-frame variability in risk markers. Here, we investigate risk marker variability in symptomatic plaques and its impact on reclassification of plaque vulnerability, as well as its association with the shape of the temporal variation over the cardiac cycle. METHODS: 56 patients with symptomatic carotid stenosis were included in this study. 88 plaques were identified and the plaque risk markers size (area), echogenicity (gray scale median, GSM) and heterogeneity (coarseness) were measured in all frames of ultrasound B-mode image sequences. Inter-frame variability was quantified using the coefficient of variation (CV). RESULTS: Inter-frame variabilities of the risk markers were area CV 5-8%; GSM CV 4-7%; coarseness CV 8-15% and was in general significantly lower in large as compared to smaller plaques. The variability in GSM risk marker caused a reclassification of vulnerability in 30 to 38% of the plaques. Temporal variations in GSM with a heart rate periodic or drift/trending pattern were found in smaller plaques (< 26 mm2), whereas random pattern was found in larger plaques. In addition, hypoechoic plaques (GSM < 25) were associated with cyclic variation pattern, independent of their size. CONCLUSIONS: Risk marker variability causes substantial reclassification of plaque vulnerability in symptomatic patients. Inter-frame variation and its temporal pattern should be considered in the design of future studies related to risk markers.

Inter-sonographer reproducibility of carotid ultrasound plaque detection using Mannheim consensus in subclinical atherosclerosis.

AIMS: To determine the inter-sonographer reproducibility of carotid ultrasound plaque detection using Mannheim consensus in a subclinical population and evaluate associations related to the reproducibility. METHODS AND RESULTS: Bilateral ultrasound screening for carotid plaques defined by Mannheim consensus was performed on 106 subclinical participants. Two different sonographers scanned the same participant, and reproducibility of plaque detection was measured by Cohens kappa. Associations with reproducibility were evaluated by comparing wall, and plaque characteristics between subjects with plaques identified in one and both scans. In general, the inter-sonographer reproducibility of plaque detection was substantial with a kappa value of 0·70 (95% CI 0·60-0·80). Plaques detected in only one scan had significantly lower plaque area and plaque thickness (6·82 mm2 and 1·45 mm) as compared to plaques detected in both scans (11·65 mm2 and 1·96 mm, P<0·001). CONCLUSION: Minor carotid plaques contribute to decreased reproducibility as compared to large plaques when screening for subclinical atherosclerosis using Mannheim consensus. Using an alternative plaque definition based on plaque thickness >1.5 mm and plaque area >10 mm2 could increase the reproducibility of plaque detection in subclinical atherosclerosis.

Visualization of asymptomatic atherosclerotic disease for optimum cardiovascular prevention (VIPVIZA): a pragmatic, open-label, randomised controlled trial.

BACKGROUND: Primary prevention of cardiovascular disease often fails because of poor adherence among practitioners and individuals to prevention guidelines. We aimed to investigate whether ultrasound-based pictorial information about subclinical carotid atherosclerosis, targeting both primary care physicians and individuals, improves prevention. METHODS: Visualization of asymptomatic atherosclerotic disease for optimum cardiovascular prevention (VIPVIZA) is a pragmatic, open-label, randomised controlled trial that was integrated within the Västerbotten Intervention Programme, an ongoing population-based cardiovascular disease prevention programme in northern Sweden. Individuals aged 40, 50, or 60 years with one or more conventional risk factors were eligible to participate. Participants underwent clinical examination, blood sampling, and ultrasound assessment of carotid intima media wall thickness and plaque formation. Participants were randomly assigned 1:1 with a computer-generated randomisation list to an intervention group (pictorial representation of carotid ultrasound plus a nurse phone call to confirm understanding) or a control group (not informed). The primary outcomes, Framingham risk score (FRS) and European systematic coronary risk evaluation (SCORE), were assessed after 1 year among participants who were followed up. This study is registered with ClinicalTrials.gov, number NCT01849575. FINDINGS: 3532 individuals were enrolled between April 29, 2013, and June 7, 2016, of which 1783 were randomly assigned to the control group and 1749 were assigned to the intervention group. 3175 participants completed the 1-year follow-up. At the 1-year follow-up, FRS and SCORE differed significantly between groups (FRS 1·07 [95% CI 0·11 to 2·03, p=0·0017] and SCORE 0·16 [0·02 to 0·30, p=0·0010]). FRS decreased from baseline to the 1-year follow-up in the intervention group and increased in the control group (-0·58 [95% CI -0·86 to -0·30] vs 0·35 [0·08 to 0·63]). SCORE increased in both groups (0·13 [95% CI 0·09 to 0·18] vs 0·27 [0·23 to 0·30]). INTERPRETATION: This study provides evidence of the contributory role of pictorial presentation of silent atherosclerosis for prevention of cardiovascular disease. It supports further development of methods to reduce the major problem of low adherence to medication and lifestyle modification. FUNDING: Västerbotten County Council, the Swedish Research Council, the Heart and Lung Foundation, the Swedish Society of Medicine, and Carl Bennet Ltd, Sweden.

Risk Marker Variability in Subclinical Carotid Plaques Based on Ultrasound is Influenced by Cardiac Phase, Echogenicity and Size.

Identification of risk markers based on quantitative ultrasound texture analysis of carotid plaques has the ability to define vulnerable components that correlate with increased cardiovascular risk. However, data describing factors with the potential to influence the measurement variability of risk markers are limited. The aim of this study was to evaluate the influence of electrocardiogram-guided image selection, plaque echogenicity and area on carotid plaque risk markers and their variability in asymptomatic carotid plaques. Plaque risk markers were measured in 57 plaques during three consecutive heartbeats at two cardiac cycle time instants corresponding to the electrocardiogram R-wave (end diastole) and end of T-wave (end systole), resulting in six measurements for each plaque. Risk marker variability was quantified by computing the coefficient of variation (CV) across the three heartbeats. The CV was significantly higher for small plaques (area <15 mm2, 10%) than for large plaques (area >15 mm2, 6%) (p < 0.001) in measurements of area, and the CV for measurements of gray-scale median were higher for echolucent plaques (<40, 15%) than for echogenic plaques (>40, 9%) (p < 0.001). No significant differences were found between systole and diastole for the mean of any risk marker or the corresponding CV value. However, in a sub-analysis, the echolucent plaques were found to have a higher CV during systole compared with diastole. The variability also caused plaque type reclassification in 16% to 25% of the plaques depending on cutoff value. The results of this study indicate that echolucent and small plaques each contribute to increased risk marker variability. Based on these results, we recommend that measurements in diastole are preferred to reduce variation, although we found that it may not be possible to characterize small plaques accurately using contemporary applied risk markers.

Role of nicotine dependence in the association between the dopamine receptor gene DRD3 and major depressive disorder.

BACKGROUND: The aims of this study were to analyze associations of dopamine receptor genes (DRD1-5) with Major Depressive Disorder (MDD) and nicotine dependence (ND), and to investigate whether ND moderates genetic influences on MDD. METHODS: The sample was ascertained from the Finnish Twin Cohort. Twin pairs concordant for smoking history were recruited along with their family members, as part of the multisite Nicotine Addiction Genetics consortium. Genetic association analyses were based on 1428 adults. Total of 70 tagging single nucleotide polymorphisms within the dopamine receptor genes were genotyped and analyzed for association with MDD, ND, and MD-ND co-morbidity. Individual level logistic regression analyses were based on 1296 adults with data on ND and MDD diagnoses, as well as on dopamine receptor genotypes adjusted for sex, age, and alcohol use. Four independent samples, such as population-based and case-control samples, were used for replication. RESULTS: Rs2399496, located 1.5 kb downstream of DRD3, showed suggestive association for MDD (p = 0.00076) and significant association for MDD-ND co-morbidity (p = 0.000079). Suggestive gene-(rs2399496) by-ND-interaction justified analyses by genetic risk variant and ND status. Individuals with ND and two minor alleles (AA) of rs2399496 had almost six-fold risk for MDD (OR 5.74, 95%CI 3.12-10.5, p = 9.010e-09) compared to individuals without ND and with two major alleles (TT). CONCLUSIONS: Significant association between a variant downstream of DRD3 and a co-morbid MDD-ND phenotype was detected. Our results further suggest that nicotine dependence may potentiate the influence of the DRD3 genetic variant on MDD.

The association between DRD2/ANKK1 and genetically informed measures of alcohol use and problems.

In 1990, Blum and colleagues first reported an association between DRD2 and alcoholism. While there have been subsequent replications of this genetic association, there have also been numerous studies that failed to detect an association between DRD2 and alcohol dependence. We propose that one aspect contributing to this inconsistency is the variation in alcohol phenotype used across studies. Within the population-based Finnish twin sample, FinnTwin16, we previously performed multivariate twin analyses to extract latent genetic factors, which account for the variation across seven measures of alcohol consumption (frequency of drinking, frequency × quantity, frequency of heavy drinking, frequency of intoxication and maximum drinks in a 24-hour period) and problems (the Rutgers Alcohol Problem Index-RAPI and the Mälmö-modified Michigan Alcohol Screen Test-MmMAST) in 3065 twins. In the present study, we examined the association between 31 DRD2/ANKK1 single-nucleotide polymorphisms (SNPs) and the genetic factor scores generated by twin analyses in a subset of FinnTwin16 (n = 602). We focus on two of the genetic factors: a general alcohol consumption and problems factor score, which represents shared genetic variance across alcohol measures, and a alcohol problems genetic factor score, which loads onto the two indices of problematic drinking (MAST and RAPI). After correction for multiple testing across SNPs and phenotypes, of the 31 SNPs genotyped across DRD2/ANKK1, one SNP (rs10891549) showed significant association with the general alcohol consumption and problems factor score (P = 0.004), and four SNPs (rs10891549, rs1554929, rs6275, rs6279), representing two independent signals after accounting for linkage disequilibrium, showed significant association with the alcohol problems genetic factor score (P = 0.005, P = 0.005, P = 0.003, P = 0.003). In this study, we provide additional positive evidence for the association between DRD2/ANKK1 and alcohol outcomes, including frequency of drinking and drinking problems. Additionally, post hoc analyses indicate stronger association signals using genetic factor scores than individual measures, which suggest that accounting for the genetic architecture of the alcohol measures reduces genetic heterogeneity in alcohol dependence outcomes in this sample and enhances the ability to detect association.

Sex-specific influence of DRD2 on ADHD-type temperament in a large population-based birth cohort.

Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder with a significant public-health impact. Previously, we described a candidate gene study in a population-based birth cohort that demonstrated an association with ADHD-affected males and the dopamine receptor D2 (DRD2). The current study evaluates potential associations of dopamine receptor genes and Cloninger temperament traits within this same sample. Participants with stringent lifetime ADHD diagnoses were ascertained systematically from the genetically isolated Northern Finland 1986 Birth Cohort (n=9432), resulting in 178 cases and 157 controls. Markers in all known dopamine receptor genes were genotyped. We report an association of DRD2 with low Persistence in females (rs1079727 P=0.02, rs1124491 P=0.02, rs1800497 P=0.03). The associated DRD2 minor allelic haplotype (CAA, P=0.03) is the same haplotype we previously associated with ADHD in males in this birth cohort. The current study further supports previous results on the role of DRD2 in individuals with ADHD. Investigations suggest that DRD2 may have an impact on both males and females, but the particular outcome appears sex-specific, manifesting as ADHD in males and low Persistence in females. Furthermore, these findings suggest that the putative role of low Persistence as an endophenotype for ADHD deserves further investigation.

Interaction of early environment, gender and genes of monoamine neurotransmission in the aetiology of depression in a large population-based Finnish birth cohort.

Objectives Depression is a worldwide leading cause of morbidity and disability. Genetic studies have recently begun to elucidate its molecular aetiology. The authors investigated candidate genes of monoamine neurotransmission and early environmental risk factors for depressiveness in the genetically isolated population-based Northern Finland Birth Cohort 1966 (12 058 live births). Design The authors ascertained and subdivided the study sample (n=5225) based on measures of early development and of social environment, and examined candidate genes of monoamine neurotransmission, many of which have shown prior evidence of a gene-environment interaction for affective disorders, namely SLC6A4, TPH2, COMT, MAOA and the dopamine receptor genes DRD1-DRD5. Results and conclusion The authors observed no major genetic effects of the analysed variants on depressiveness. However, when measures of early development and of social environment were considered, some evidence of interaction was observed. Allelic variants of COMT interacted with high early developmental risk (p=0.005 for rs2239393 and p=0.02 for rs4680) so that the association with depression was detected only in individuals at high developmental risk group (p=0.0046 and ß=0.056 for rs5993883-rs2239393-rs4680 risk haplotype CGG including Val158), particularly in males (p=0.0053 and ß=0.083 for the haplotype CGG). Rs4274224 from DRD2 interacted with gender (p=0.017) showing a significant association with depressiveness in males (p=0.0006 and ß=0.0023; p=0.00005 and ß=0.069 for rs4648318-rs4274224 haplotype GG). The results support the role of genes of monoamine neurotransmission in the aetiology of depression conditional on environmental risk and sex, but not direct major effects of monoaminergic genes in this unselected population.

Impact of temperament on depression and anxiety symptoms and depressive disorder in a population-based birth cohort.

BACKGROUND: The aim of this study was to characterize at the population level how innate features of temperament relate to experience of depressive mood and anxiety, and whether these symptoms have separable temperamental backgrounds. METHODS: The study subjects were 4773 members of the population-based Northern Finland Birth Cohort 1966, a culturally and genetically homogeneous study sample. Temperament was measured at age 31 using the temperament items of the Temperament and Character Inventory and a separate Pessimism score. Depressive mood was assessed based on a previous diagnosis of depressive disorder or symptoms of depression according to the Hopkins Symptom Check List - 25. Anxiety was assessed analogously. RESULTS: High levels of Harm avoidance and Pessimism were related to both depressive mood (effect sizes; d=0.84 and d=1.25, respectively) and depressive disorder (d=0.68 and d=0.68, respectively). Of the dimensions of Harm avoidance, Anticipatory worry and Fatigability had the strongest effects. Symptoms of depression and anxiety showed very similar underlying temperament patterns. LIMITATIONS: Although Harm avoidance and Pessimism appear to be important endophenotype candidates for depression and anxiety, their potential usefulness as endophenotypes, and whether they meet all the suggested criteria for endophenotypes will remain to be confirmed in future studies. CONCLUSIONS: Personality characteristics of Pessimism and Harm avoidance, in particular its dimensions Anticipatory worry and Fatigability, are strongly related to symptoms of depression and anxiety as well as to depressive disorder in this population. These temperamental features may be used as dimensional susceptibility factors in etiological studies of depression, which may aid in the development of improved clinical practice.

A population-based association study of candidate genes for depression and sleep disturbance.

The clinical manifestation of depression comprises a variety of symptoms, including early morning awakenings and fatigue, features also indicating disturbed sleep. The presence or absence of these symptoms may reflect differences in neurobiological processes leading to prolonged depression. Several neurobiological mechanisms have been indicated in the induction of depression, including disturbances in serotonergic and glutamatergic neurotransmission and in the action of the hypothalamic-pituitary-adrenal (HPA) axis. The same transmitters have also been linked to sleep regulation. We hypothesized that depression without simultaneous symptoms of disturbed sleep would partly have a different genetic background than depression with symptoms of disturbed sleep. We tested this hypothesis using a systematic population-based association study of 14 candidate genes related to depression and disturbed sleep. Association of genetic variants with either depression alone, depression with early morning awakenings, or depression with fatigue was investigated using permutation-based allelic association analysis of a sample of 1,654 adults recruited from Finland's population-based program. The major findings were associations of TPH2 (rs12229394) with depression accompanied by fatigue in women and CREB1 (rs11904814) with depression alone in men. We also found suggestive associations in women for GAD1, GRIA3, and BDNF with depression accompanied by fatigue, and for CRHR1 with depression accompanied by early morning awakenings. The results indicate sex-dependent and symptom-specific differences in the genetic background of depression. These differences may partially explain the broad spectrum of depressive symptoms, and their systematic monitoring could potentially be used for diagnostic purposes.