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1. Identifying causal variants by fine mapping across multiple studies

   https://doi.org/10.1371/journal.pgen.1009733  

   LaPierre, Nathan; Taraszka, Kodi; Huang, Helen; He, Rosemary; Hormozdiari, Farhad; Eskin, Eleazar (September 2021, PLOS Genetics)

   Zeggini, Eleftheria (Ed.)

   Increasingly large Genome-Wide Association Studies (GWAS) have yielded numerous variants associated with many complex traits, motivating the development of “fine mapping” methods to identify which of the associated variants are causal. Additionally, GWAS of the same trait for different populations are increasingly available, raising the possibility of refining fine mapping results further by leveraging different linkage disequilibrium (LD) structures across studies. Here, we introduce multiple study causal variants identification in associated regions (MsCAVIAR), a method that extends the popular CAVIAR fine mapping framework to a multiple study setting using a random effects model. MsCAVIAR only requires summary statistics and LD as input, accounts for uncertainty in association statistics using a multivariate normal model, allows for multiple causal variants at a locus, and explicitly models the possibility of different SNP effect sizes in different populations. We demonstrate the efficacy of MsCAVIAR in both a simulation study and a trans-ethnic, trans-biobank fine mapping analysis of High Density Lipoprotein (HDL). 

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2. Multi-resolution localization of causal variants across the genome

   https://doi.org/10.1038/s41467-020-14791-2  

   Sesia, Matteo; Katsevich, Eugene; Bates, Stephen; Candès, Emmanuel; Sabatti, Chiara (February 2020, Nature Communications)

   Abstract In the statistical analysis of genome-wide association data, it is challenging to precisely localize the variants that affect complex traits, due to linkage disequilibrium, and to maximize power while limiting spurious findings. Here we report onKnockoffZoom: a flexible method that localizes causal variants at multiple resolutions by testing the conditional associations of genetic segments of decreasing width, while provably controlling the false discovery rate. Our method utilizes artificial genotypes as negative controls and is equally valid for quantitative and binary phenotypes, without requiring any assumptions about their genetic architectures. Instead, we rely on well-established genetic models of linkage disequilibrium. We demonstrate that our method can detect more associations than mixed effects models and achieve fine-mapping precision, at comparable computational cost. Lastly, we applyKnockoffZoomto data from 350k subjects in the UK Biobank and report many new findings. 

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3. Diversity, divergence and density: How habitat and hybrid zone dynamics maintain a genomic cline in an intertidal barnacle

   https://doi.org/10.1111/jbi.14142  

   Wares, John_P; Strand, Allan_E; Sotka, Erik_E (June 2021, Journal of Biogeography)

   Abstract AimAs within‐species genomic data have been shown useful in interpreting broader biogeographic trends, we analysed the mode of population genomic isolation involved in a well‐studied intertidal genomic cline to better understand the mechanisms maintaining it. These results were interpreted in the context of spatial variation in habitat use and availability as well as likely fitness consequences for hybridization between the two lineages. LocationPacific coast of North America. TaxonArthropods (Class Maxillopoda, Order Sessilia, Family Balanidae;Balanus glandula). MethodsGenotype‐by‐sequencing approaches were used to generate single‐nucleotide polymorphism markers across sites sampled between southern Alaska and Southern California. Inference using standard population genomic methods, including analysis of population structure, inbreeding and linkage disequilibrium, was used to identify the steepest transitions across the largest number of loci examined. These data were put in the context of observed population density and habitat availability. ResultsWe show that the majority of markers analysed show strong clinal transitions in a very narrow portion of the California coast. Patterns of linkage disequilibrium among markers, along with prior evidence of variation in reproductive potential by latitude and by mitochondrial lineage, suggest some reproductive isolation among the northern and southern lineages ofB. glandulathat are concordant with the drop in population density and habitat availability in central California. Main ConclusionsA significant clinal transition in genomic diversity is stronger and more localized than previously recognized and exhibits statistical patterns suggesting that the lineages are reproductively and phenotypically distinct in ways that may be ecologically important. As this species has been used to infer process in coastal biogeography, further study of concordant patterns will be important for advancing our understanding of this region. 

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4. Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance

   https://doi.org/10.1186/s13195-023-01376-6  

   Mei, Hao; Simino, Jeannette; Li, Lianna; Jiang, Fan; Bis, Joshua C.; Davies, Gail; Hill, W. David; Xia, Charley; Gudnason, Vilmundur; Yang, Qiong; et al (January 2024, Alzheimer's Research & Therapy)

   Abstract BackgroundUncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. MethodsWe performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. ResultsThe single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. ConclusionsVDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals. 

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5. Founder effects shape linkage disequilibrium and genomic diversity of a partially clonal invader

   https://doi.org/10.1111/mec.15854  

   Flanagan, Ben A.; Krueger‐Hadfield, Stacy A.; Murren, Courtney J.; Nice, Chris C.; Strand, Allan E.; Sotka, Erik E. (April 2021, Molecular Ecology)

   Abstract The genomic variation of an invasive species may be affected by complex demographic histories and evolutionary changes during the invasion. Here, we describe the relative influence of bottlenecks, clonality, and population expansion in determining genomic variability of the widespread red macroalgaAgarophyton vermiculophyllum. Its introduction from mainland Japan to the estuaries of North America and Europe coincided with shifts from predominantly sexual to partially clonal reproduction and rapid adaptive evolution. A survey of 62,285 SNPs for 351 individuals from 35 populations, aligned to 24 chromosome‐length scaffolds indicate that linkage disequilibrium (LD), observed heterozygosity (H_o), Tajima's D, and nucleotide diversity (Pi) were greater among non‐native than native populations. Evolutionary simulations indicate LD and Tajima's D were consistent with a severe population bottleneck. Also, the increased rate of clonal reproduction in the non‐native range could not have produced the observed patterns by itself but may have magnified the bottleneck effect on LD. Elevated marker diversity in the genetic source populations could have contributed to the increasedH_oand Pi observed in the non‐native range. We refined the previous invasion source region to a ~50 km section of northeastern Honshu Island. Outlier detection methods failed to reveal any consistently differentiated loci shared among invaded regions, probably because of the complexA. vermiculophyllumdemographic history. Our results reinforce the importance of demographic history, specifically founder effects, in driving genomic variation of invasive populations, even when localized adaptive evolution and reproductive system shifts are observed. 

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