Mono- and biallelic variant effects on disease at biobank scale.

Identifying causal factors for Mendelian and common diseases is an ongoing challenge in medical genetics1. Population bottleneck events, such as those that occurred in the history of the Finnish population, enrich some homozygous variants to higher frequencies, which facilitates the identification of variants that cause diseases with recessive inheritance2,3. Here we examine the homozygous and heterozygous effects of 44,370 coding variants on 2,444 disease phenotypes using data from the nationwide electronic health records of 176,899 Finnish individuals. We find associations for homozygous genotypes across a broad spectrum of phenotypes, including known associations with retinal dystrophy and novel associations with adult-onset cataract and female infertility. Of the recessive disease associations that we identify, 13 out of 20 would have been missed by the additive model that is typically used in genome-wide association studies. We use these results to find many known Mendelian variants whose inheritance cannot be adequately described by a conventional definition of dominant or recessive. In particular, we find variants that are known to cause diseases with recessive inheritance with significant heterozygous phenotypic effects. Similarly, we find presumed benign variants with disease effects. Our results show how biobanks, particularly in founder populations, can broaden our understanding of complex dosage effects of Mendelian variants on disease.

The validity of rheumatoid arthritis diagnoses in Finnish biobanks.

OBJECTIVE: The aim of this study was to determine the validity of rheumatoid arthritis (RA) diagnoses in patients participating in Finnish biobanks. METHOD: We reviewed the electronic medical records of 500 Finnish biobank participants: 125 patients with at least one visit with a diagnosis of seropositive RA, 125 patients with at least one visit with a diagnosis of seronegative RA, and 250 age- and gender-matched controls. The patients were chosen from five different biobank hospitals in Finland. A rheumatologist reviewed the medical records to assess whether each patients' diagnosis was correct. The diagnosis was compared with the diagnostic codes in the Finnish Care Register for Health Care (CRHC) and special reimbursement data of the Social Insurance Institution of Finland. RESULTS: The positive predictive value (PPV) of CRHC diagnosis of RA (for seropositive and seronegative RA combined) was 0.82. For patients with a special reimbursement for anti-rheumatic medications for RA, the PPV was 0.89. The PPV was higher in patients with more than one visit. For one, two, five, and 10 visits, the PPV was 0.82, 0.85, 0.89, and 0.90, respectively, and for patients who also had the special reimbursement, the PPV was 0.89, 0.91, 0.93, and 0.94 for one, two, five, and 10 visits, respectively. In patients positive for anti-citrullinated protein antibodies, the PPV was 0.98. CONCLUSION: These results demonstrate that the validity of RA diagnoses in Finnish biobanks was good and can be further improved by including data on special reimbursement for medication, number of visits, and serological data.

Role of inflammation markers in the prediction of weight gain and development of obesity in adults - A prospective study.

BACKGROUND AND AIMS: There is a growing body of literature confirming the association between inflammation and obesity. Recent research suggests that inflammation may play a role in weight gain. The aim of the study was to analyse whether serum inflammatory markers predict weight gain or development of obesity in a prospective study design. METHODS AND RESULTS: The baseline study (DILGOM 2007) consists of a population-based sample of 5024 Finnish men and women aged 25-75 years, of whom 3735 participated in the follow-up study in 2014. Baseline data collection included a questionnaire on health behaviour, physical examinations and blood samples including serum high-sensitivity C-Reactive Protein (hs-CRP), Interleukin-1 receptor antagonist (IL-1Ra), Interleukin-6 (IL-6), Tumor Necrosis Factor Alpha (TNF-alpha) and high molecular weight adiponectin (HMW adiponectin). Indicators of obesity were weight, body mass index (BMI), waist circumference and body fat percentage (% body fat). At baseline hs-CRP, IL-1Ra, IL-6, TNF-alpha and HMW adiponectin associated strongly (p < 0.0001) with obesity indicators. After adjustment for several potential predictors of obesity, hs-CRP and IL-1Ra associated inversely with changes in obesity indicators during the 7-year follow-up. These associations disappeared, however, after further adjustment for baseline BMI. Only HMW adiponectin retained a modest positive association with the change in weight (p = 0.008), in BMI (p = 0.007) and in waist circumference (p = 0.002). CONCLUSION: These findings suggest that the inflammatory markers, although highly associated with obesity, do not predict weight gain in an adult population. This could translate into inflammation being a result of obesity rather than a contributing factor to it.

Missing Teeth Predict Incident Cardiovascular Events, Diabetes, and Death.

Periodontitis, the main cause of tooth loss in the middle-aged and elderly, associates with the risk of atherosclerotic vascular disease. The objective was to study the capability of the number of missing teeth in predicting incident cardiovascular diseases (CVDs), diabetes, and all-cause death. The National FINRISK 1997 Study is a Finnish population-based survey of 8,446 subjects with 13 y of follow-up. Dental status was recorded at baseline in a clinical examination by a trained nurse, and information on incident CVD events, diabetes, and death was obtained via national registers. The registered CVD events included coronary heart disease events, acute myocardial infarction, and stroke. In Cox regression analyses, having ≥5 teeth missing was associated with 60% to 140% increased hazard for incident coronary heart disease events (P < 0.020) and acute myocardial infarction (P < 0.010). Incident CVD (P < 0.043), diabetes (P < 0.040), and death of any cause (P < 0.019) were associated with ≥9 missing teeth. No association with stroke was observed. Adding information on missing teeth to established risk factors improved risk discrimination of death (P = 0.0128) and provided a statistically significant net reclassification improvement for all studied end points. Even a few missing teeth may indicate an increased risk of CVD, diabetes, or all-cause mortality. When individual risk factors for chronic diseases are assessed, the number of missing teeth could be a useful additional indicator for general medical practitioners.

The healthy Nordic diet and incidence of Type 2 Diabetes--10-year follow-up.

Studies have shown that a diet of healthy foods typical of Nordic countries has a beneficial effect on risk factors for Type 2 Diabetes (T2D), such as obesity and low-grade inflammation. However, longitudinal epidemiological studies examining the association between the healthy Nordic diet and T2D are lacking.

Evaluation of HLA-DRB1 imputation using a Finnish dataset.

Owing to the vast amount of alleles, high-resolution human leukocyte antigen (HLA) typing is expensive and time-consuming. Scientists have attempted to develop computational approaches to define HLA alleles with high confidence. We tested the reliability of HLA*IMP and SNP2HLA for imputing HLA-DRB1 alleles in a Finnish material (n=161). The per-individual success rates varied between 16.68% and 25.4% using both softwares. One of the most prominent example was HLA-DRB1*01:01 allele showing approximately a 30% success rate while being the most common wrongly imputed allele. In Finland, isolation and migration history have shaped the gene pool narrower showing HLA haplotype frequencies typical to the Finnish population when compared to Europeans. The imputation success for HLA-DRB1 alleles was very low pointing to the importance of population-specific reference material.

Egg consumption patterns and Salmonella risk in Finland.

To estimate the consumer risk of contracting Salmonella infection via shell eggs and to evaluate the effect of possible preventative measures, quantitative microbiological risk assessment is being developed in Finland. As a part of the risk assessment, a survey of 918 respondents was conducted to study how households purchase, store, handle, and use eggs. In addition, suitability of the Internet as a survey method was compared with a postal survey. Shell eggs were usually purchased once every 2 weeks (41% of all the respondents). Ninety-one percent of the respondents bought eggs in groceries and 93% stored eggs at chilled temperatures. The majority of the respondents (80%) only had eggs in their home for which the best-before date had not expired. Only 34% of the respondents said that they always washed their hands after breaking eggs. Consumption of well-cooked eggs accounted for 84%, consumption of soft-boiled eggs for 12%, and consumption of raw eggs for 4% of the total amount of eggs consumed. The elderly used eggs more frequently than the whole population, but the consumption of raw egg dishes decreased with age. The Internet survey was a rapid method for transmitting information, but its response rate was low (9%), and it did not appear to be a suitable tool for data collection in a general population. The results indicate that although the majority of the respondents had safe egg-handling practices, a substantial minority of the consumers had risk-prone behavior.