Although the genetic origin of many human diseases and phenotypes has been long and widely recognized, identification of the causative gene alleles has been limited, slow, and cumbersome. This has ...changed substantially with the introduction of genome-wide association studies (GWASs) a decade ago, fueled by studies and reference projects of human genetic diversity and the development of novel DNA analysis technology applicable to high-throughput and large-scale data generation. Although GWASs essentially combine epidemiological study designs with molecular genetic analysis techniques, it has also fundamentally changed the way in which research was done in human genetics by the introduction of large consortia of collaborating investigators. GWASs have over flooded many clinical and basic research areas with gene discoveries, including those in reproductive medicine. This review describes aspects of GWAS methodology and how this field of human genetics is developing.
Antidepressant use has been associated with increased fall risk. Antidepressant-related adverse drug reactions (e.g. orthostatic hypotension) depend partly on genetic variation. We hypothesized that ...candidate genetic polymorphisms are associated with fall risk in older antidepressant users.
The association between antidepressant use and falls was cross-sectionally investigated in a cohort of Dutch older adults by logistic regression analyses. In case of significant interaction product term of antidepressant use and candidate polymorphism, the association between the variant genotype and fall risk was assessed within antidepressant users and the association between antidepressant use and fall risk was investigated stratified per genotype. Secondly, a look-up of the candidate genes was performed in an existing genome-wide association study on drug-related falls in antidepressant users within the UK Biobank. In antidepressant users, genetic associations for our candidate polymorphisms for fall history were investigated.
In antidepressant users(n = 566), for rs28371725 (CYP2D6*41) fall risk was decreased in TC/variant allele carriers compared to CC/non-variant allele carriers (OR = 0.45, 95% CI 0.26-0.80). Concerning rs1057910 (CYP2C9*3), fall risk was increased in CA/variant allele carriers compared to AA/non-variant allele carriers (OR = 1.95, 95% CI 1.17-3.27). Regarding, rs1045642 (ABCB1), fall risk was increased in AG/variant allele carriers compared to GG/non-variant allele carriers (OR = 1.69, 95% CI 1.07-2.69). Concerning the ABCB1-haplotype (rs1045642/rs1128503), fall risk was increased in AA-AA/variant allele carriers compared to GG-GG/non-variant allele carriers (OR = 1.86, 95% CI 1.05-3.29). In the UK Biobank, in antidepressant users(n = 34,000) T/variant-allele of rs28371725 (CYP2D*41) was associated with increased fall risk (OR = 1.06, 95% CI 1.01-1.12). G/non-variant-allele of rs4244285 (CY2C19*2) was associated with decreased risk (OR = 0.96, 95% CI 0.92-1.00).
This is the first study showing that certain genetic variants modify antidepressant-related fall risk. The results were not always consistent across the studies and should be validated in a study with a prospective design. However, pharmacogenetics might have value in antidepressant (de)prescribing in falls prevention.
The incidence of all non-vertebral fractures, as well as the relation to bone mineral density (BMD), was quantified in 7806 men and women from the Rotterdam Study, a prospective, population-based ...cohort study of men and women aged 55 years and older. In addition, the sensitivity of using a
T-score at or below −2.5 for identifying subjects at risk for fractures was assessed.
At baseline, between 1990 and 1993, femoral neck BMD was measured by dual energy X-ray absorptiometry (DXA). Subsequently, gender-specific
T-scores were calculated using the NHANES reference population. During a mean follow-up of 6.8 years, information on incident non-vertebral fractures was gathered.
In general, hip, wrist and upper humerus fractures are the most frequent fractures in both men and women. Femoral neck BMD appears to be an equally important risk factor in both genders, and is especially related to hip fractures. For all non-vertebral fractures, the age-adjusted hazard ratio (95% confidence interval) per standard deviation decrease in femoral neck BMD was 1.5 (1.4–1.6) for women and 1.4 (1.2–1.6) for men. For hip fractures, the hazard ratios were 2.1 (1.7–2.5) for women and 2.3 (1.6–3.3) for men.
Only 44% of all non-vertebral fractures occurred in women with a
T-score below −2.5; in men, this percentage was even lower (21%). Thus, there is a clear need for the development of more sensitive risk assessment tools, using not only BMD, but also other clinical predictors of fractures.
The urinary tract is inhabited by a diversity of microorganisms, known as the genitourinary microbiota. Here, we investigated the association between the use of antimicrobial drugs and the ...composition of the genitourinary microbiota.
Clean-catch urinary samples were collected from 27 participants of the Rotterdam Study. Bacterial DNA was extracted and the 16S ribosomal RNA gene variable regions V3 and V4 were analyzed using Illumina sequencing. 23 of the 27 participants were included in the analysis. The population consisted of 10 men and 13 women with a mean age of 75 ± 3 years. The time between the last prescription of an antimicrobial drug and sampling was determined and categorized. The use of antimicrobial drugs prior to urine sampling was associated with statistically significant differences in the beta-diversity of the genitourinary microbiota. No association was found between antimicrobial drug use and the alpha-diversity of the genitourinary microbiota. Operational Taxonomic Units (OTUs) that were lowest in participants who used antimicrobial drug belonged to Lactobacillus and Finegoldia. In contrast, an OTU belonging to the genus Parabacteroides had higher abundances. Also, an OTU belonging to the species E.coli was higher in the participants who used antimicrobial drugs.
Prior use of antimicrobial drugs is associated with a different composition of the genitourinary microbiota. Our results might indicate a persisting effect of antimicrobial drugs on the composition of the microbiota, but reverse causality cannot be ruled out. Future studies are needed to differentiate between two possibilities. Genitourinary dysbiosis could be the result of antimicrobial drug use or genitourinary dysbiosis could be a risk factor for urinary tract infections resulting in increased use of antimicrobial drugs. This may have important implications for treatment and prevention of (recurrent) UTIs.
To develop and validate a prognostic model for incident knee osteoarthritis (KOA) in a general population and determine the value of different risk factor groups to prediction.
The prognostic model ...was developed in 2628 individuals from the Rotterdam Study-I (RS-I). Univariate and multivariate analyses were performed for questionnaire/easily obtainable variables, imaging variables, genetic and biochemical markers. The extended multivariate model was tested on discrimination (receiver operating characteristic curve and area under the curve (AUC)) in two other population-based cohorts: Rotterdam Study-II and Chingford Study.
In RS-I, there was moderate predictive value for incident KOA based on the genetic score alone in subjects aged <65 years (AUC 0.65), while it was only 0.55 for subjects aged ≥65 years. The AUC for gender, age and body mass index (BMI) in prediction for KOA was 0.66. Addition of the questionnaire variables, genetic score or biochemical marker urinary C-terminal cross-linked telopeptide of type II collagen to the model did not change the AUC. However, when adding the knee baseline KL score to the model the AUC increased to 0.79. Applying external validation, similar results were observed in the Rotterdam Study-II and the Chingford Study.
Easy obtainable 'Questionnaire' variables, genetic markers, OA at other joint sites and biochemical markers add only modestly to the prediction of KOA incidence using age, gender and BMI in an elderly population. Doubtful minor radiographic degenerative features in the knee, however, are a very strong predictor of future KOA. This is an important finding, as many radiologists do not report minor degenerative changes in the knee.
Antimicrobial drugs are known to have effects on the human gut microbiota. We studied the long-term temporal relationship between several antimicrobial drug groups and the composition of the human ...gut microbiota determined in feces samples.
Feces samples were obtained from a community-dwelling cohort of middle-aged and elderly individuals (Rotterdam Study). Bacterial DNA was isolated and sequenced using V3/V4 16 S ribosomal RNA sequencing (Illumina MiSeq). The time between the last prescription of several antimicrobial drug groups and the day of sampling was categorized into 0-12, 12-24, 24-48 and >48 months. The effects of the antimicrobial drug groups on the Shannon alpha-diversity (diversity), the Bray-Curtis beta-diversity (community structure), the Firmicutes/Bacteroidetes (F/B) ratio and individual genera were determined.
We studied the gut microbiota of 1413 individuals (57.5% female, median age 62.6 years). The alpha-diversity was significantly lower up to 4 years after prescriptions of macrolides and lincosamides. It was also lower in the first year after the use of beta-lactams. The community structure (beta-diversity) of the microbiota was significantly different up to 4 years for macrolides and lincosamides, the first year for beta-lactams and at least the first year for quinolones. For the F/B ratio, drugs with a high anaerobic activity shifted the ratio toward Firmicutes in the first year whereas other antimicrobial drugs shifted the ratio toward Bacteroidetes.
Use of antimicrobial drugs is associated with a shift in the composition of the gut microbiota.These effects differ in strength and duration, depending on the antimicrobial drug group used. These findings should be considered when prescribing antimicrobial drugs.
The first generation of genome-wide association studies (GWA studies) for psychiatric disorders has led to new insights regarding the genetic architecture of these disorders. We now start to realize ...that a larger number of genes, each with a small contribution, are likely to explain the heritability of psychiatric diseases. The contribution of a large number of genes to complex traits can be analyzed with genome-wide profiling. In a discovery sample, a genetic risk profile for depression was defined based on a GWA study of 1738 adult cases and 1802 controls. The genetic risk scores were tested in two population-based samples of elderly participants. The genetic risk profiles were evaluated for depression and anxiety in the Rotterdam Study cohort and the Erasmus Rucphen Family (ERF) study. The genetic risk scores were significantly associated with different measures of depression and explained up to ∼0.7% of the variance in depression in Rotterdam Study and up to ∼1% in ERF study. The genetic score for depression was also significantly associated with anxiety explaining up to 2.1% in Rotterdam study. These findings suggest the presence of many genetic loci of small effect that influence both depression and anxiety. Remarkably, the predictive value of these profiles was as large in the sample of elderly participants as in the middle-aged samples.
To establish the prevalence of osteoporosis, vertebral fractures (VFs), and non-VFs in acromegaly patients with long-term controlled disease and factors potentially influencing fracture risk.
...Case-control study. Patients and measurements Eighty-nine patients (46% male, mean age: 58 years) were included. We studied VFs and non-VFs, bone mineral density (BMD), and markers of bone turnover. In 48 patients, BMD assessment was also obtained 7 years prior to the current study. To compare VF prevalence, data from a sample of the Dutch population (n=3469) were used.
VF prevalence was 59% (men 64% and women 54%), significantly increased when compared with controls (odds ratio up to 6.5), and independent of the duration of disease control, BMD, markers of bone turnover, and acromegalic disease characteristics. Mean number of VFs per patient was 3.4±0.3 (range 1-8). There was no relationship between the number and severity of fractures, parameters of bone turnover, and follow-up BMD measurements. BMD did not change during prolongation of follow-up by 7 years of controlled acromegaly.
There is a very high prevalence of VFs in acromegaly patients with long-term controlled disease, independently of BMD. In view of the significant morbidity and mortality associated with VFs in general and the inability of BMD to predict fracture risk in acromegalic patients, we propose to include VF assessment, for example by lateral conventional radiographs of the spine in the screening of patients with acromegaly, both at diagnosis and during follow-up after establishment of disease control.
The effects of vitamin D in the elderly are inconsistent. The aim of this study was to evaluate the association between vitamin D status and the metabolic syndrome (MetS) in the elderly, as well as ...between vitamin D status and the components of MetS (i.e. serum glucose, triglycerides (TG), HDL cholesterol (HDL-C), waist circumference (WC), and blood pressure (BP)).
The study was embedded in the Rotterdam Study, a population-based cohort of middle-aged and elderly adults. We analyzed data from 3240 people (median age 71.2 years) who did not have type 2 diabetes mellitus at baseline.
We found higher 25-hydroxyvitamin D (25(OH)D) concentrations associated with lower prevalence of MetS (odds ratio (OR); 95% CI: 0.61; 0.49, 0.77 for adequate levels (≥75 nmol/l) vs deficiency (<50 nmol/l). In addition, in analysis of the individual components, the ORs for adequate vs deficient vitamin D levels were: 0.66 (95% CI 0.53, 0.83) for elevated WC, 0.67 (95% CI 0.52, 0.86) for reduced HDL-C, 0.69 (95% CI 0.54, 0.88) for elevated TG, and 0.80 (95% CI 0.65, 0.99) for elevated fasting glucose. Vitamin D was not associated with elevated blood pressure, and ORs for adequacy vs deficiency were 0.82 (95% CI 0.65, 1.03).
Higher 25(OH)D concentrations in the elderly are associated with lower prevalence of MetS and, in particular, with more beneficial HDL-C, TG, WC, and serum glucose. Since the prevalence of vitamin D deficiency is common worldwide and its risk increases with age, if causality is proven, benefits of improving vitamin D status among the elderly may be great.
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