A named General Practitioner (GP) is associated with an increase of hospital days in a single predictor analysis: a follow-up of 15 years.

BACKGROUND: Continuity of care constitutes the basis of primary health care services and is associated with decreased hospitalization. In Finland, accessibility to primary care and increased use of hospital services are recognized challenges for the health care system. OBJECTIVES: The aim of the study was to determine whether having a named GP is associated with hospital service use. METHODS: The data are part of the Health and Social Support study (HeSSup) based on a random Finnish working-age population sample. The cohort of the study comprised participants of postal surveys in 1998 (n = 25,898) who returned follow-up questionnaires both in 2003 and 2012 (n = 11,924). Background characteristics were inquired in the questionnaires, and hospitalization was derived from national registries (Hilmo-register). RESULTS: A named GP was reported both in 2003 and 2012 only by 34.3% of the participants. The association between hospital days and a named GP was linearly rising and statistically significant in a single predictor model. The strongest associations with hospital use were with health-related factors, and the association with a named GP was no longer significant in multinomial analysis. CONCLUSION: A named GP is associated with an increased use of hospital days, but in a multinomial analysis the association disappeared. Health related factors showed the strongest association with hospital days. From the perspective of the on-going Finnish health and social services reform, continuity of care should be emphasized.

A named GP increases self-reported access to health care services.

BACKGROUND: Continuity of care strengthens health promotion and decreases mortality, although the mechanisms of these effects are still unclear. In recent decades, continuity of care and accessibility of health care services have both decreased in Finland. OBJECTIVES: The aim of the study was to investigate whether a named and assigned GP representing continuity of care is associated with the use of primary and hospital health care services and to create knowledge on the state of continuity of care in a changing health care system in Finland. METHODS: The data are part of the Health and Social Support (HeSSup) mail survey based on a random Finnish working age population sample of 64,797 individuals drawn in 1998 and follow-up surveys in 2003 and 2012. The response rate in 1998 was 40% (n = 25,898). Continuity of care was derived from the 2003 and 2012 data sets, other variables from the 2012 survey (n = 11,924). The principal outcome variables were primary health care and hospital service use reported by participants. The association of the explanatory variables (gender, age, education, reported chronic diseases, health status, smoking, obesity, NYHA class of any functional limitation, depressive mood and continuity of care) with the outcome variables was analysed by binomial logistic regression analysis. RESULTS: A named and assigned GP was independently and significantly associated with more frequent use of primary and hospital care in the adjusted logistic regression analysis (ORs 1.53 (95% CI 1.35-1.72) and 1.19 (95% CI 1.08-1.32), p < 0.001). CONCLUSION: A named GPs is associated with an increased use of primary care and hospital services. A named GP assures access to health care services especially to the chronically ill population. The results depict the state of continuity of care in Finland. All benefits of continuity of care are not enabled although it still assures treatment of population in the most vulnerable position.

Stroke and cardiovascular risk factors among working-aged Finnish migraineurs.

BACKGROUND: The aim of our study was to evaluate the risk for comorbid cardio- and cerebrovascular diseases in the working-aged migraine population of Finland. METHODS: A total of 1505 cases who reported diagnosed migraine and 3010 controls from a cohort of 11,596 cases in the Finnish Health and Social Support Study were included. The study material was linked with two registers. ICD diagnoses I63 for ischemic stroke (IS), I21 - I22 for acute myocardial infarction (AMI), and G43 for transient ischemic attack (TIA) among study participants were drawn from the national Finnish Care Register for Health Care at the follow-up in 2012. Reimbursed triptan prescriptions were drawn from the national Social Security Institution (SII) data. The self-reported vascular risk factors were hypertension, high cholesterol values, any diabetes, myocardial infarction, stroke, and TIA. Odds Ratios (OR) with 95% confidence (95% CI) intervals were assessed for diagnosed stroke, myocardial infarction, and TIA. RESULTS: Migraineurs were mostly female (82%) and ≥ 54 years old (62%). Triptans were reimbursed among 34.7% of migraineurs. A self-reported hypertension (21%), high serum cholesterol (38%), and any diabetes (7%) were more common among migraineurs vs controls (p < 0.05). There was no risk for AMI. The risk for TIA (OR 3.20, 95% CI 1.45-7.05) and IS (2.57, 95% CI 1.28-5.17) among migraineurs vs controls remained high after adjustment for self-reported hypertension, obesity, and smoking. The risk was higher among women in two groups ≥54 years (3.25, 95% CI 1.35-7.84 and 5.0, 95% CI 1.94-12.89, respectively). The average age for IS in migraine was 57.5 years and for TIA 58.2 years among women, and 52.8 years and 50.3 years among men, respectively. CONCLUSION: Cardiovascular risk should be screened in the aging migraine population, and hormonal and other migraine-related risk factors should be considered, especially among women. Efficacious attack treatment with triptans should be offered to migraine patients who do not show contraindications.

Research orientation among general practitioners compared to other specialties.

OBJECTIVE: The volume of research work done by general practitioners (GP) is modest compared to other specialties. In order to find out reasons for this we examined the current situation concerning research orientation and factors relating to them among Finnish GPs compared to other specialists. DESIGN AND SETTING: Data from The Physician 2018 Study were used for our research. The study was undertaken in collaboration with all five medical faculties in Finland and the Finnish Medical Association. It compiled information on physicians` social background, work history and career and research plans as well as their views regarding undergraduate and specialist training, values, and professional identity. SUBJECTS: The basic study population comprised all Finnish doctors under 70 years of age (N = 23,131). Questionnaires were sent to doctors born on even-numbered days (n = 11,336). Altogether 5,214 (45.8%) responded. Responses from GPs (n = 796) were compared with those of doctors in other specialties (n = 3,514). MAIN OUTCOME MEASURES AND RESULTS: The respondents were asked about their current intention to undertake a doctoral degree. Factors associated with this were analysed. Only 7.3% of GPs had completed a doctoral degree. The corresponding figure in other specialties was 32.3% (p < 0.001). In general practice the current intention to undertake a doctoral degree had only slightly increased over ten years. Most GPs had also decided not to undertake a doctorate. The main factors associated with the current intention to complete a doctoral degree were interest in attaining a senior position (OR 3.43, 95% CI 2.25-5.24), a position in a university hospital district (OR 2.89, 95% CI 1.69-4.94) or other sector than primary care (OR 1.87, 95% CI 1.18-2.96), one's father being a doctor (OR 2.01, 95% CI 1.09-3.72) and male gender (OR 1.63, 95% CI 1.05-2.54). CONCLUSION: Research work in primary health care has been quite sparse. In general practice there is a need to increase teaching and guidance in research work.Key pointsResearch work in primary health care is not very common.Only 7.3% of GPs had completed their doctorate compared to 32.3% in other specialties.A main factor associated with the current intention to complete a doctoral degree was interest in attaining a senior position.

Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10-7), an immunoglobulin gene whose antibodies interact with ß-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10-7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10-6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

Correction: Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Intrahepatic cholestasis of pregnancy and comorbidity: A 44-year follow-up study.

INTRODUCTION: Intrahepatic cholestasis of pregnancy (ICP) is a reversible liver disorder occurring during pregnancy. It has a typical genetic background with known genetic mutations and can be considered an expression of this genetic predisposition. The objective of this study was to determine whether ICP is associated with specific long-term comorbidity. MATERIAL AND METHODS: The study population comprised 571 women with ICP in at least one pregnancy who were compared with 1333 pregnant women without ICP during 1969-1988 at Tampere University Hospital, Finland. The cohort's follow-up time was 44 years. All ICD-10 classification discharge diagnoses were examined for the women in the ICP group from 1998 to 2013 and ICD-10 diagnoses from outpatient care from 1969 to 2013. RESULTS: At least one disease of the digestive system had been diagnosed in 50.4% (288/571) of the ICP mothers compared with 34.4% (459/1333) of the reference group (P < 0.001). In a more detailed analysis, women with a history of ICP had an increased risk for cholelithiasis and/or cholecystitis (odds ratio [OR] 2.88, 95% confidence interval [CI] 2.17 to 3.84), diseases of the pancreas (OR 2.26, 95% CI 1.20 to 4.27) and hypothyroidism (OR 2.38, 95% CI 1.27 to 4.46) compared with the reference group. Arterial diseases were less common in the ICP mothers than in the reference group (OR 0.38, 95% CI .15 to .99). Regarding other diseases, there were no statistically significant differences between the ICP mothers and reference group. CONCLUSIONS: Half of the women with a history of ICP were diagnosed with at least one disease of the digestive system compared with a third in the reference group. The risk of cholelithiasis, cholecystitis, diseases of the pancreas and hypothyroidism was increased compared with the reference group. These are important facts when counseling women after a pregnancy with ICP. Also, this is of importance for the general practitioners and other physicians who take care of these women.

Long-term survival after intrahepatic cholestasis of pregnancy: A follow-up of 571 mothers.

OBJECTIVE: Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder during pregnancy. ICP has been associated with morbidity but little is known about women's long-term survival. Our aim was to determine whether ICP is associated with mothers' long-term survival. STUDY DESIGN: The study population comprised 571 women with ICP in at least one pregnancy seen at Tampere University Hospital in Finland between 1969‒1988. The reference group comprised 1333 women: the previous and the following participant in the maternity ward diary. The data were obtained from Statistics Finland in March 2017 containing deaths among the study participants between 1971‒2015. The follow-up time of the cohort was 27-46 years. The Kaplan-Meier method was used. RESULTS: Totally, 39 of the mothers with ICP (6.8%) and 111 of the reference group (8.3%) had died by the end of 2015 (p = 0.267). The mean survival time of ICP women was 77.4 years and of the reference group 79.2 years (p = 0.288). The mean survival time from labour in the ICP group was 45.0 years and in the reference group 44.8 years (p = 0.259). CONCLUSIONS: Based on this study ICP does not seem to be associated with women's survival. There is no need to follow-up ICP mothers' health because of the nonexistent risk of premature death.

The association between bullying victimization in childhood and fibromyalgia. Data from the nationwide Finnish health and social support (HeSSup) study based on a sample of 64,797 individuals.

BACKGROUND: Fibromyalgia is a functional pain syndrome presenting with various psychological symptoms. Several studies have shown that adverse life events are associated with fibromyalgia. The aim of the current study is to explore the association between self-reported bullying victimization in childhood and self-reported fibromyalgia in adulthood. METHODS: The basic study setting is cross-sectional - with focused use of retrospective data - derived from a large on-going postal follow up survey (sample N = 64,797) initiated in Finland in 1998. Only respondents having answered the questions on fibromyalgia in both follow ups in 2003 and 2012 were included (N = 11,924). Severity of bullying was divided into three groups starting from no bullying followed by minor and severe bullying. Covariates having shown statistically significant associations with fibromyalgia in cross tabulation using Pearson's chi-squared test were included in the final multiple logistic regression analyses. RESULTS: In our study, 50.6% of the respondents reported victimization of minor and 19.6% of severe bullying in childhood. Participants reporting fibromyalgia in adulthood reported more bullying, and in females alone this association was statistically significant (p = .027). In multiple logistic regression analysis statistically significant associations between bullying victimization in childhood (reference: no bullying) and fibromyalgia were found: adjusted odds ratio (OR) for minor bullying was 1.35 (95% CI 1.09-1.67) and for severe bullying 1.58 (95% CI 1.21-2.06). However, in log-linear and logistic regression interaction models the association between bullying and fibromyalgia was not statistically significant when depression was included in the models. CONCLUSIONS: Our results suggest that peer bullying victimization might be associated with fibromyalgia. However, in logistic log linear and logistic interaction models there was no statistically significant association when depression was included. As a result, there is need for further, preferably prospective cohort studies. The findings also emphasize the importance of actions to prevent childhood bullying.

Primary health care in transition: Variations in service profiles of general practitioners in Estonia and in Finland between 1993 and 2012.

INTRODUCTION: Since the early 1990s, the Estonian and Finnish health systems have undergone various changes which are expected to have impacted the type and range of services provided by general practitioners (GPs). OBJECTIVE: To compare GP services between Estonia and Finland in 1993 and 2012 and draw a parallel with transformations occurred in the health systems of both countries during these two decades. METHODS: Data were collected through surveys among 129 and 288 GPs from Estonia and Finland in 2012 and 139 Estonian and 239 Finnish GPs in 1993. Descriptive statistics were used to compare between countries and years. RESULTS: Between 1993 and 2012, the number of working hours per week and consultations per day increased in Estonia and decreased in Finland. In 2012, GPs in were more often the first contact for psychosocial and women´s and children´s in Estonia, whereas this decreased in Finland. The frequency of treating acute patients mostly decreased in both countries. We observed a decrease in medical procedures in Finland and an increase in Estonia. Finnish GPs still conducted more procedures in 2012. CONCLUSION: Due to partly opposite changes, the services provided by Finnish and Estonian GPs became more similar. Still, there are large differences in services provided, possibly arising from differences in the organisation of health services, the training of doctors and patients' preferences.

Intrahepatic cholestasis of pregnancy and associated causes of death: a cohort study with follow-up of 27-46 years.

BACKGROUND: The aim of this study was to determine whether intrahepatic cholestasis of pregnancy (ICP) is associated with causes of death during on average 35 years follow-up after the delivery. METHODS: The study population comprised 571 women with ICP in at least one pregnancy seen at Tampere University Hospital, Finland, between 1969 and 1988. ICP was verified from patient records. The previous and following subjects in the maternity ward diary were taken as controls for each ICP case. In total, there were 1333 controls. All underlying causes of death were obtained from Statistics Finland in March 2017. The deaths occurred during 1971-2015 and the causes of death were classified according to ICD-10. RESULTS: Altogether, 39 of the mothers with ICP (6.8%) and 111 of the controls (8.3%) had died by the end of 2015 (p = 0.267). There were more underlying causes of death from gastrointestinal diseases (15%) in the ICP group than in the control group (4%) (p = 0.011). The number of underlying causes of death due to diseases of the circulatory system were lower in the ICP group (13%) than in the control group (26%), although the finding was not statistically significant (p = 0.088). Moreover, neoplasms were the underlying cause of death in 46% of cases among mothers with ICP and in 41% of cases among the controls (p = 0.609). Diseases of the other organ systems were rare in both groups. CONCLUSION: Women with a history of ICP do not have an increased overall mortality. However, deaths from gastrointestinal diseases are overrepresented among women with a history of ICP.

Analysis of factors associated with waiting times for GP appointments in Finnish health centres: a QUALICOPC study.

OBJECTIVE: Access to care is a multidimensional concept, considered as a structural aspect of health care quality; it reflects the functioning of a health care organization. The aim of this study was to investigate patients' experiences of access to care and to analyse factors associated with waiting times to GP appointments at Finnish health centres. A questionnaire survey was addressed to Finnish GPs within the Quality and Costs of Primary Care in Europe study framework. Two to nine patients per GP completed the questionnaire, altogether 1196. Main outcome measures were waiting times for appointments with GPs and factors associated with waiting times. In addition, patients' opinions of access to appointments were analysed. RESULTS: Of the 988 patients who had made their appointment in advance, 84.9% considered it easy to secure an appointment, with 51.9% obtaining an appointment within 1 week. Age and reason for contact were the most significant factors affecting the waiting time. Elderly patients tended to have longer waiting times than younger ones, even when reporting illness as their reason for contact. Thus, waiting times for appointments tend to be prolonged in particular for the elderly and there is room for improvement in the future.

The relationship between childhood adversities and fibromyalgia in the general population.

BACKGROUND: Fibromyalgia is a syndrome characterized by widespread pain and a variety of somatic symptoms. The international prevalence of fibromyalgia is 2-5%, but its current prevalence in Finland is unclear. Various adversities are linked to the onset of fibromyalgia. However, there is need for more data regarding the association between childhood physical abuse and fibromyalgia. Further, the association of childhood emotional stressors and fibromyalgia is disputed. The aim of the current study is to produce more information about that relationship using data from the Health and Social Support (HeSSup) Study. METHODS: HeSSup is a postal study consisting of a random sample of the Finnish population. The study setting is cross-sectional. Participants in the study were asked if they have been diagnosed with fibromyalgia. Those responding affirmatively were classified as fibromyalgia patients. Six childhood adversities were enquired, and the relationship between fibromyalgia and these events were analysed by cross tabulation and logistic regression. RESULTS: There were associations between examined adversities and fibromyalgia before and after adjustments for demographic features and depression (being afraid of a family member: odds ratio after adjustment 1.60, 95% CI 1.28-2.01; long-lasting financial difficulties 1.45, 1.18-1.77; serious conflicts in the family 1.40, 1.14-1.72; parental divorce 1.34, 1.05-1.72; serious or chronic illnesses in the family 1.27, 1.05-1.55; alcohol problems in the family 1.25, 1.02-1.53). CONCLUSION: All six enquired adversities were associated with fibromyalgia after adjustments. These findings emphasize the importance of preventing adverse childhood experiences.

What predicts doctors' satisfaction with their chosen medical specialty? A Finnish national study.

BACKGROUND: In Finland the number of medical specialists varies between specialties and regions. More regulation of the post-graduate medical training is planned. Therefore, it is important to clarify what predicts doctors' satisfaction with their chosen specialty. METHODS: A random sample contained 50% of all Finnish doctors under 70 years of age. The respose rate was 50.5%. Working-age specialists were asked to value their motives when choosing a specialty. They were also asked if they would choose the same specialty again. The odds ratios for not choosing the same specialty again were tested. RESULTS: Diversity of work was the most important motive (74% of respondents). Seventeen percent of GPs would not choose the same specialty again, compared to 2% of ophthalmologists and 4% of pediatricians. A major role of Diversity of work and Prestigious field correlated with satisfaction whereas Chance with dissatisfaction with the specialty. DISCUSSION: Motives and issues related to the work and training best correlate with satisfaction with the specialty. CONCLUSIONS: When the numbers of Finnish postgraduate medical training posts become regulated, a renewed focus should be given to finding the most suitable speciality for each doctor. Information about employment and career advice should play an important role in this.

Men's Health Is Not Affected by Their Mothers' Intrahepatic Cholestasis of Pregnancy.

Little is known about the effects of mother's intrahepatic cholestasis of pregnancy (ICP) on the health of sons born to these mothers. The purpose of the present study was to explore the health of sons born to mothers with ICP. The study design was a retrospective study of ICP mothers' sons. In the region of Tampere University Hospital in Finland, 365 sons of mothers with ICP during 1969 to 1988 and 617 sons of mothers without ICP were sent a questionnaire in 2010. The response rates were 37.8% (n = 138) and 36.6% (n = 226), respectively. Only minor differences were reported between the two groups. Self-evaluated health was similar. There were no significant differences between the groups regarding symptoms and complaints, diagnosed diseases, mental health, and use of medicines. Cough was 10.8 percentage points less common among ICP mothers' sons than among controls (p = .034). Urticaria was more common among ICP mothers' sons, the difference in percentage points being 2.2 (p = .026). In general, a mother's ICP does not affect her son's health.

Factors important in the choice of a medical career: a Finnish national study.

BACKGROUND: Applying for medical school is the first and also one of the most important career choices a physician makes. It is important to understand the reasons behind this decision if we are to choose the best applicants for medical schools and enable them to pursue satisfying careers. METHODS: Respondents to the Finnish Junior Physician 88, Physician 1998 and Physician 2008 studies were asked: "To what extent did the following factors influence your decision to apply for medical school?" In 1998 and 2008 the respondents were also asked: "If you were starting your studies now, would you start studying medicine?" and had to answer "Yes" or "No". The odds ratios for the answer "No" were tested using logistic regression models. RESULTS: "Interest in people" was the main motive for starting to study medicine. "Good salary" and "Prestigious profession" were more important motives for males and "Vocation" and "Interest in people" for females. There were some significant changes in the motives for entering medicine in the 20-year period between studies. "Vocation" and "Wide range of professional opportunities" as important motives for entering medicine predicted satisfaction with the medical profession. DISCUSSION: Strong inner motivation may indicate the ability to adapt to the demands of work as a physician. CONCLUSIONS: Medical schools should try to select those applicants with the greatest vocational inclination towards a medical career.

Weaker Self-Esteem in Adolescence Predicts Smoking.

BACKGROUND: To study whether weaker self-esteem in adolescence is connected with smoking behavior in adulthood. METHODS: An age cohort born in 1979 responded to the Lawrence Self-Esteem Questionnaire (LAWSEQ) at the age of 16 (n = 1,072). Respondents' smoking behavior was monitored annually during adolescence and 75.3% (n = 813) of them remained nonsmokers during adolescence. A follow-up questionnaire eliciting smoking behavior was sent to the adolescent nonsmokers at the age of 29 years. Response rate at follow-up was 46.2% (n = 376). RESULTS: Weaker self-esteem (LAWSEQ score ≥ 3) during the adolescence was not significantly associated with smoking in adulthood. However, those respondents who had weaker self-esteem in adolescence had increased risk of having been smoking regularly (adjusted OR 1.8, 95% CI 1.1-3.0) although not all of them were smokers at the time of the follow-up. CONCLUSIONS: Those with weaker self-esteem in adolescence are more likely to smoke regularly in adulthood.

[Finnish language proficiency of immigrant physicians in medical licensure examinations]. / Maahanmuuttajataustaisten lääkärien suomen kielen taito laillistamiskuulustelussa.

BACKGROUND: Physicians immigrating to Finland from countries outside the EU/EEA must pass a language test and three medical licensure examinations (MLE) in Finnish. Failing rates are high and remarkably variable. MATERIAL AND METHODS: MLE examination papers were analyzed with linguistic criteria: writing skills and word frequency. Results of the linguistic analyses were compared with the MLE scores. RESULTS: Better results in writing skills analysis correlate with higher scores in MLE. Also a higher portion of rare words correlates with higher scores in MLE. CONCLUSIONS: The mandatory language test does not serve as a valid measurement tool for immigrant physicians.

Flawed oral health of a non-smoking adolescent suggests smoking in adulthood.

BACKGROUND: Smokers often have oral health problems. We studied whether poor oral health among non-smoking adolescents is connected to smoking behaviour in adulthood. METHODS: We used an age cohort born in 1979 (n = 2582) taking part in annual oral health check-ups between the ages of 13 and 15. Self-reported non-smokers were used as the study population. As measures we used decayed, missing or filled teeth/surfaces (DMF) and decayed teeth (D) and smoking behaviour at ages 13-15 and the depending measure was smoking behaviour at the age of 29. RESULTS: Those who were non-smokers at ages 13-15 and had tooth decay (D > 0) in an oral check-up during that period had higher risk (OR (Odds Ratio) 1.88, 95% confidence interval 1.2-2.9) of being a smoker by age 29. Tooth decay at age 15 predicted earlier onset of smoking for those, who became smokers later in life. Dental caries (DMF > 0) was not associated with higher risk of becoming a smoking adult, but those with dental caries at age 13 were more likely to start smoking earlier. CONCLUSIONS: Poorer dental health, especially tooth decay in adolescence is a possible indicator of a greater likelihood of transforming from being a non-smoker to a smoker. Dentists should notice this for allocated health promotion.

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.