2017 William Allan Award Introduction : Kari Stefansson

Peer reviewe

Estimation of the Multiple Testing Burden for Genomewide Association Studies of Common Variants

Genomewide association studies are an exciting strategy in genetics, recently becoming feasible. While pioneering studies are being underway, it is already clear that the analytic issue of determining the significance of results presents a challenge to the wide community of researchers. Rather than each study engaging in independent evaluation, there is need in the community to have standards set for whole-genome significance. 
We have therefore undertaken the task of developing such standards, based on data collected with collaborators in the International Haplotype Map Consortium. We report an estimated burden of a million independent tests genomewide in Europeans, and twice that number in Africans. We further identify the sensitivity of the testing burden to the required significance level, with implications to staged design of association studies.
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Stochastic Rainfall-runoff Model with Explicit Soil Moisture Dynamics

Stream runoff is perhaps the most poorly represented process in ecohydrological stochastic soil moisture models. Here we present a rainfall-runoff model with a new stochastic description of runoff linked to soil moisture dynamics. We describe the rainfall-runoff system as the joint probability density function (PDF) of rainfall, soil moisture and runoff forced by random, instantaneous jumps of rainfall. We develop a master equation for the soil moisture PDF that accounts explicitly for a general state-dependent rainfall-runoff transformation. This framework is then used to derive the joint rainfall-runoff and soil moisture-runoff PDFs. Runoff is initiated by a soil moisture threshold and a linear progressive partitioning of rainfall based on the soil moisture status. We explore the dependence of the PDFs on the rainfall occurrence PDF (homogeneous or state-dependent Poisson process) and the rainfall magnitude PDF (exponential or mixed-exponential distribution). We calibrate the model to 63 years of rainfall and runoff data from the Upper Little Tennessee watershed (USA) and show how the new model can reproduce the measured runoff PDF

Meta-analysis fine-mapping is often miscalibrated at single-variant resolution

Meta-analysis is pervasively used to combine multiple genome-wide association studies (GWASs). Fine-mapping of meta-analysis studies is typically performed as in a single-cohort study. Here, we first demonstrate that heterogeneity (e.g., of sample size, phenotyping, imputation) hurts calibration of meta-analysis fine-mapping. We propose a summary statistics-based quality-control (QC) method, suspicious loci analysis of meta-analysis summary statistics (SLALOM), that identifies suspicious loci for meta-analysis fine-mapping by detecting outliers in association statistics. We validate SLALOM in simulations and the GWAS Catalog. Applying SLALOM to 14 meta-analyses from the Global Biobank Meta-analysis Initiative (GBMI), we find that 67% of loci show suspicious patterns that call into question fine-mapping accuracy. These predicted suspicious loci are significantly depleted for having nonsynonymous variants as lead variant (2.7×; Fisher's exact p = 7.3 × 10−4). We find limited evidence of fine-mapping improvement in the GBMI meta-analyses compared with individual biobanks. We urge extreme caution when interpreting fine-mapping results from meta-analysis of heterogeneous cohorts.</p

The critical needs and challenges for genetic architecture studies in Africa

Human genetic studies have long been vastly Eurocentric, raising a key question about the generalizability of these study findings to other populations. Because humans originated in Africa, these populations retain more genetic diversity, and yet individuals of African descent have been tremendously underrepresented in genetic studies. The diversity in Africa affords ample opportunities to improve fine-mapping resolution for associated loci, discover novel genetic associations with phenotypes, build more generalizable genetic risk prediction models, and better understand the genetic architecture of complex traits and diseases subject to varying environmental pressures. Thus, it is both ethically and scientifically imperative that geneticists globally surmount challenges that have limited progress in African genetic studies to date. Additionally, African investigators need to be meaningfully included, as greater inclusivity and enhanced research capacity afford enormous opportunities to accelerate genomic discoveries that translate more effectively to all populations. We review the advantages, challenges, and examples of genetic architecture studies of complex traits and diseases in Africa. For example, with greater genetic diversity comes greater ancestral heterogeneity; this higher level of understudied diversity can yield novel genetic findings, but some methods that assume homogeneous population structure and work well in European populations may work less well in the presence of greater heterogeneity in African populations. Consequently, we advocate for methodological development that will accelerate studies important for all populations, especially those currently underrepresented in genetics.Peer reviewe

Base-specific mutational intolerance near splice sites clarifies the role of nonessential splice nucleotides

Variation in RNA splicing (i.e., alternative splicing) plays an important role in many diseases. Variants near 5' and 3' splice sites often affect splicing, but the effects of these variants on splicing and disease have not been fully characterized beyond the two "essential" splice nucleotides flanking each exon. Here we provide quantitative measurements of tolerance to mutational disruptions by position and reference allele-alternative allele combinations. We show that certain reference alleles are particularly sensitive to mutations, regardless of the alternative alleles into which they are mutated. Using public RNA-seq data, we demonstrate that individuals carrying such variants have significantly lower levels of the correctly spliced transcript, compared to individuals without them, and confirm that these specific substitutions are highly enriched for known Mendelian mutations. Our results propose a more refined definition of the "splice region" and offer a new way to prioritize and provide functional interpretation of variants identified in diagnostic sequencing and association studies.Peer reviewe

Polygenic burden in focal and generalized epilepsies

Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64 x 10(-15); Cleveland: P = 2.85 x 10(-4); Finnish-ancestry Epi25: P = 1.80 x 10(-4)) or population controls (Epi25: P = 2.35 x 10(-70); Cleveland: P = 1.43 x 10(-7); Finnish-ancestry Epi25: P = 3.11 x 10(-4); UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99 x 10(-4)). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74 x 10(-19); Cleveland: P = 1.69 x 10(-6)). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60 x 10(-15); Cleveland: P = 1.39 x 10(-2)). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls-in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.Peer reviewe