The contribution of genetic inheritance in multiple sclerosis was established early on. Although multiple sclerosis is not a Mendelian disease, its incidence and prevalence is higher in family ...members of affected individuals compared with the general population. Throughout the last decade, several small studies failed to identify any robust genetic associations besides the classic associations in the major histocompatibility complex region. During the past few years, genome-wide association studies (GWAS) have revolutionized the genetics of multiple sclerosis, uncovering more than 200 implicated genetic loci. Here, we describe these main findings and discuss the new avenues that these discoveries lay open.
Clinical trials have been the main tool used by the health sciences community to test and evaluate interventions. Trials can fall into two broad categories: pragmatic and explanatory. Pragmatic ...trials are designed to evaluate the effectiveness of interventions in real-life routine practice conditions, whereas explanatory trials aim to test whether an intervention works under optimal situations. Pragmatic trials produce results that can be generalized and applied in routine practice settings. Since most results from exploratory trials fail to be broadly generalizable, the "pragmatic design" has gained momentum. This review describes the concept of pragmatism, and explains in particular that there is a continuum between pragmatic and explanatory trials, rather than a dichotomy. Special focus is put on the limitations of the pragmatic trials, while recognizing the importance for and impact of this design on medical practice.
Most autoimmune-disease-risk effects identified by genome-wide association studies (GWAS) localize to open chromatin with gene-regulatory activity. GWAS loci are also enriched in expression ...quantitative trait loci (eQTLs), thus suggesting that most risk variants alter gene expression. However, because causal variants are difficult to identify, and cis-eQTLs occur frequently, it remains challenging to identify specific instances of disease-relevant changes to gene regulation. Here, we used a novel joint likelihood framework with higher resolution than that of previous methods to identify loci where autoimmune-disease risk and an eQTL are driven by a single shared genetic effect. Using eQTLs from three major immune subpopulations, we found shared effects in only ∼25% of the loci examined. Thus, we show that a fraction of gene-regulatory changes suggest strong mechanistic hypotheses for disease risk, but we conclude that most risk mechanisms are not likely to involve changes in basal gene expression.
Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to ...identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4(+) T-cell subsets, regulatory T cells, CD8(+) T cells, B cells, and monocytes. We find that ∼90% of causal variants are non-coding, with ∼60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10-20% directly alter recognizable transcription factor binding motifs. Rather, most non-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
John Ioannidis, Nikolaos Patsopoulos, and Evangelos Evangelou argue that, although meta-analyses often measure heterogeneity between studies, these estimates can have large uncertainty, which must be ...taken into account when interpreting evidence
Multiple sclerosis (MS) is an inflammatory neurodegenerative disease with genetic predisposition. Over the last decade, genome-wide association studies with increasing sample size led to the ...discovery of robustly associated genetic variants at an exponential rate. More than 200 genetic loci have been associated with MS susceptibility and almost half of its heritability can be accounted for. However, many challenges and unknowns remain. Definitive studies of disease progression and endophenotypes are yet to be performed, whereas the majority of the identified MS variants are not yet functionally characterized. Despite these shortcomings, the unraveling of MS genetics has opened up a new chapter on our understanding MS causal mechanisms.
Background Several approaches are available for evaluating heterogeneity in meta-analysis. Sensitivity analyses are often used, but these are often implemented in various non-standardized ways. ...Methods We developed and implemented sequential and combinatorial algorithms that evaluate the change in between-study heterogeneity as one or more studies are excluded from the calculations. The algorithms exclude studies aiming to achieve either the maximum or the minimum final I2 below a desired pre-set threshold. We applied these algorithms in databases of meta-analyses of binary outcome and ≥4 studies from Cochrane Database of Systematic Reviews (Issue 4, 2005, n = 1011) and meta-analyses of genetic associations (n = 50). Two I2 thresholds were used (50% and 25%). Results Both algorithms have succeeded in achieving the pre-specified final I2 thresholds. Differences in the number of excluded studies varied from 0% to 6% depending on the database and the heterogeneity threshold, while it was common to exclude different specific studies. Among meta-analyses with initial I2 > 50%, in the large majority 19 (90.5%) and 208 (85.9%) in genetic and Cochrane meta-analyses, respectively exclusion of one or two studies sufficed to decrease I2 < 50%. Similarly, among meta-analyses with initial I2 > 25%, in most cases 16 (57.1%) and 382 (81.3%), respectively) exclusion of one or two studies sufficed to decrease heterogeneity even <25%. The number of excluded studies correlated modestly with initial estimated I2 (correlation coefficients 0.52–0.68 depending on algorithm used). Conclusions The proposed algorithms can be routinely applied in meta-analyses as standardized sensitivity analyses for heterogeneity. Caution is needed evaluating post hoc which specific studies are responsible for the heterogeneity.
To extend our understanding of the genetic basis of human immune function and dysfunction, we performed an expression quantitative trait locus (eQTL) study of purified CD4+ T cells and monocytes, ...representing adaptive and innate immunity, in a multi-ethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. We note an over-representation of T cell–specific eQTLs among susceptibility alleles for autoimmune diseases and of monocyte-specific eQTLs among Alzheimer's and Parkinson's disease variants. This polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants.
Meta-analysis is the systematic and quantitative synthesis of effect sizes and the exploration of their diversity across different studies. Meta-analyses are increasingly applied to synthesize data ...from genome-wide association (GWA) studies and from other teams that try to replicate the genetic variants that emerge from such investigations. Between-study heterogeneity is important to document and may point to interesting leads.
To exemplify these issues, we used data from three GWA studies on type 2 diabetes and their replication efforts where meta-analyses of all data using fixed effects methods (not incorporating between-study heterogeneity) have already been published. We considered 11 polymorphisms that at least one of the three teams has suggested as susceptibility loci for type 2 diabetes. The I2 inconsistency metric (measuring the amount of heterogeneity not due to chance) was different from 0 (no detectable heterogeneity) for 6 of the 11 genetic variants; inconsistency was moderate to very large (I2 = 32-77%) for 5 of them. For these 5 polymorphisms, random effects calculations incorporating between-study heterogeneity revealed more conservative p-values for the summary effects compared with the fixed effects calculations. These 5 associations were perused in detail to highlight potential explanations for between-study heterogeneity. These include identification of a marker for a correlated phenotype (e.g. FTO rs8050136 being associated with type 2 diabetes through its effect on obesity); differential linkage disequilibrium across studies of the identified genetic markers with the respective culprit polymorphisms (e.g., possibly the case for CDKAL1 polymorphisms or for rs9300039 and markers in linkage disequilibrium, as shown by additional studies); and potential bias. Results were largely similar, when we treated the discovery and replication data from each GWA investigation as separate studies.
Between-study heterogeneity is useful to document in the synthesis of data from GWA investigations and can offer valuable insights for further clarification of gene-disease associations.
Symptoms of attention deficit hyperactivity disorder (ADHD), diagnosed mainly in children, often persist into adulthood. Adults in this group have a high rate of other psychiatric problems and ...functional difficulties in a number of key areas such as academic achievement, interpersonal relationships, and employment. Although the usefulness of immediate-release methylphenidate in children has been extensively studied, studies in adults, which are few, demonstrate varying results.
To evaluate the efficacy and tolerability of immediate-release methylphenidate versus placebo in the treatment of adults with ADHD.
We searched the following databases in November 2013: CENTRAL, Ovid MEDLINE, EMBASE, PsycINFO, Database of Abstracts of Reviews of Effects (DARE), and two trials registers. Biosis was searched in December 2013. We inspected references of all relevant papers to identify more studies and contacted authors of recently published trials.
We included all randomized trials comparing immediate-release methylphenidate versus placebo in participants aged 18 years or older with ADHD. We excluded trials conducted on subpopulations of adults with ADHD such as adults with both ADHD and substance dependence.
Two review authors independently selected trials, extracted data, and assessed trial risk of bias. We contacted authors of trials to ask for additional and missing data. For dichotomous outcomes, we calculated risk ratios (RRs) and 95% confidence intervals (CIs). For continuous outcomes, we calculated mean differences (MDs) or standardized mean differences (SMDs) with 95% CIs.
Results from the 11 randomized controlled trials (474 participants, counting participants from cross-over studies as a single arm, and counting both arms from parallel studies) included in the review demonstrated improvement in core clinical ADHD symptoms of hyperactivity, impulsivity, and inattentiveness, and overall improvement. We were able to pool results from 10 studies, which included 466 participants.Most included studies were judged to have unclear risk of bias for most categories. However, as all studies were randomized, double-blind, and placebo-controlled and, in general, did not contain factors that significantly decreased the quality of the body of evidence, the quality of evidence was assessed as "high" for most outcomes according to the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach. For one outcome-inattentiveness-most information came from studies at unclear risk of bias, and so the quality of evidence for this outcome was judged as "moderate."Results are given as SMD for each of the core clinical symptoms of ADHD. In all cases, participant numbers were calculated by counting participants in a single arm from cross-over studies and in both arms from parallel studies. The SMD for the outcome of hyperactivity was -0.60 (95% CI -1.11 to -0.09, 6 studies, number of participants (n) = 245, high-quality evidence) in favor of immediate-release methylphenidate; the SMD for impulsivity was -0.62 (95% CI -1.08 to -0.17, 5 studies, n = 207, high-quality evidence) in favor of immediate-release methylphenidate; and the SMD for inattentiveness was -0.66 (95% CI -1.02 to -0.30, 7 studies, n = 391, moderate-quality evidence) in favor of immediate-release methylphenidate. Moderate to extreme statistical heterogeneity was detected for all outcomes. Subgroup analysis comparing high versus low doses did not indicate that higher doses of immediate-release methylphenidate were associated with greater efficacy.For overall change, the SMD was -0.72 (95% CI -1.12 to -0.32, 9 studies, n = 455, high-quality evidence) in favor of immediate-release methylphenidate.The effects of immediate-release methylphenidate on anxiety and depression as parameters of general changes in mental state were equivocal. Some trials reported reduction in depression and anxiety, others detailed no change, and still others described an increase in depressive and anxious symptoms.The most common adverse effect was loss of appetite, in some cases with weight loss. Although no study reported either of these effects as problematic or severe, the included studies were of short duration; thus clinical significance could not be properly assessed. Five studies reported changes in systolic or diastolic blood pressure, and three reported increases in heart rate. None of these results were judged to present cause for concern. No study reported clinically significant adverse effects-cardiovascular or other. Three studies did not mention adverse effects. We were unable to determine whether adverse effects were not discussed by study authors because none occurred, or because no data on adverse effects were collected.
Data from randomized controlled trials suggest that immediate-release methylphenidate is efficacious for treating adults with ADHD with symptoms of hyperactivity, impulsivity, and inattentiveness, and for improving their overall clinical condition. Trial data suggest that adverse effects from immediate-release methylphenidate for adults with ADHD are not of serious clinical significance, although this conclusion may be limited, certainly in the case of weight loss, by the short duration of published studies.
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