Family-based GWAS for dental class I malocclusion and clefts.

BACKGROUND: Individuals born with cleft lip and/or palate who receive corrective surgery regularly have abnormal growth in the midface region such that they exhibit premaxillary hypoplasia. However, there are also genetic contributions to craniofacial morphology in the midface region, so although these individuals appear to have Class III skeletal discrepancy, their molar relationship may be Class I. Past genome-wide association studies (GWASs) on skeletal Class II and III malocclusion suggested that multiple genetic markers contribute to these phenotypes via a multifactorial inheritance model, but research has yet to examine the genetic markers associated with dental Class I malocclusion. Thus, our goal was to conduct a family based GWAS to identify genes across the genome that are associated with Class I malocclusion, as defined by molar relations, in humans with and without clefts. METHODS: Our cohort consisted of 739 individuals from 47 Filipino families originally recruited in 2006 to investigate the genetic basis of orofacial clefts. All individuals supplied blood samples for DNA extraction and genotyping, and a 5,766 single nucleotide polymorphism (SNP) custom panel was used for the analyses. We performed a transmission disequilibrium test for participants with and without clefts to identify genetic contributors potentially involved with Class I malocclusion. RESULTS: In the total cohort, 13 SNPs had associations that reached the genomic control threshold (p < 0.005), while five SNPs were associated with Class I in the cohort of participants without clefts, including four associations that were identified in the total cohort. The associations for the SNPs ABCA4 rs952499, SOX1-OT rs726455, and RORA rs877228 are of particular interest, as past research found associations between these genes and various craniofacial phenotypes, including cleft lip and/or palate. CONCLUSIONS: These findings support the multifactorial inheritance model for dental Class I malocclusion and suggest a common genetic basis for different aspects of craniofacial development.

Natural variation in root traits identifies significant SNPs and candidate genes for phosphate deficiency tolerance in Zea mays L.

Phosphorus (P) is a crucial macronutrient required for normal plant growth. Its effective uptake from the soil is a trait of agronomic importance. Natural variation in maize (339 accessions) root traits, namely root length and number of primary, seminal, and crown roots, root and shoot phosphate (Pi) contents, and root-to-shoot Pi translocation (root: shoot Pi) under normal (control, 40 ppm) and low phosphate (LP, 1 ppm) conditions, were used for genome-wide association studies (GWAS). The Bayesian-information and Linkage-disequilibrium Iteratively Nested Keyway (BLINK) model of GWAS provided 23 single nucleotide polymorphisms (SNPs) and 12 relevant candidate genes putatively linked with root Pi, root: shoot Pi, and crown root number (CRN) under LP. The DNA-protein interaction analysis of Zm00001d002842, Zm00001d002837, Zm00001d002843 for root Pi, and Zm00001d044312, Zm00001d045550, Zm00001d025915, Zm00001d044313, Zm00001d051842 for root: shoot Pi, and Zm00001d031561, Zm00001d001803, and Zm00001d001804 for CRN showed the presence of potential binding sites of key transcription factors like MYB62, bZIP11, ARF4, ARF7, ARF10 and ARF16 known for induction/suppression of phosphate starvation response (PHR). The in-silico RNA-seq analysis revealed up or down-regulation of candidate genes along with key transcription factors of PHR, while Uniprot analysis provided genetic relatedness. Candidate genes that may play a role in P uptake and root-to-shoot Pi translocation under LP are proposed using common PHR signaling components like MYB62, ARF4, ARF7, ARF10, ARF16, and bZIP11 to induce changes in root growth in maize. Candidate genes may be used to improve low P tolerance in maize using the CRISPR strategy.

Sumbawa cattle: a study of growth hormone (GH) gene variants and their association with biometric traits.

The growth hormone (GH) gene plays a vital role in regulating animal metabolism and body size, making it a potential candidate for influencing livestock performance. This study aimed to investigate the polymorphisms within the GH gene and their associations with 10 biometric traits in the Sumbawa cattle population of Indonesia. Biometric trait data and blood samples were collected from 112 Sumbawa cattle individuals, and their GH gene sequences were analyzed using two sets of primers for amplification. Seven single nucleotide polymorphisms (SNPs) were identified in the GH gene: g.442C>T, g.446G>C, g.558C>T, g.649C>A, g.1492C>A, g.1510C>A, and g.1578G>A. All SNPs were located in the intronic region except for SNP g.558C>T, which was found in the coding sequence (CDS) region. The SNP g.558C>T is classified as a synonymous variant. Haplotype analysis revealed a strong linkage disequilibrium between SNPs g.558C>T and g.649C>A. Distributions of genotypes and alleles of all SNPs were in agreement with the Hardy-Weinberg equilibrium (p > 0.05, χ2 < 15.56), except for SNPs g.446G>C and g.1492C>A. The association study showed that the SNP g.442C>T significantly (p < 0.05) affected HL, BL, SH, and PH traits in Sumbawa cattle. Additionally, the g.446G>C and g.558C>T were also found to be associated with PH and CC traits, respectively. The polymorphisms detected in the GH gene could have implications for selection programs to enhance desired biometric traits in Sumbawa cattle. Improving livestock productivity can be done by understanding genetic diversity and its relationship with phenotypic characteristics.

Unraveling the complex role of MAPT-containing H1 and H2 haplotypes in neurodegenerative diseases.

A ~ 1 Mb inversion polymorphism exists within the 17q21.31 locus of the human genome as direct (H1) and inverted (H2) haplotype clades. This inversion region demonstrates high linkage disequilibrium, but the frequency of each haplotype differs across ancestries. While the H1 haplotype exists in all populations and shows a normal pattern of genetic variability and recombination, the H2 haplotype is enriched in European ancestry populations, is less frequent in African ancestry populations, and nearly absent in East Asian ancestry populations. H1 is a known risk factor for several neurodegenerative diseases, and has been associated with many other traits, suggesting its importance in cellular phenotypes of the brain and entire body. Conversely, H2 is protective for these diseases, but is associated with predisposition to recurrent microdeletion syndromes and neurodevelopmental disorders such as autism. Many single nucleotide variants and copy number variants define H1/H2 haplotypes and sub-haplotypes, but identifying the causal variant(s) for specific diseases and phenotypes is complex due to the extended linkage equilibrium. In this review, we assess the current knowledge of this inversion region regarding genomic structure, gene expression, cellular phenotypes, and disease association. We discuss recent discoveries and challenges, evaluate gaps in knowledge, and highlight the importance of understanding the effect of the 17q21.31 haplotypes to promote advances in precision medicine and drug discovery for several diseases.

Falls, fracture and frailty risk in multiple sclerosis: a Mendelian Randomization study to identify shared genetics.

INTRODUCTION: Patients with multiple sclerosis (MS) commonly present musculoskeletal disorders characterized by lower bone mineral density (BMD) and muscle weakness. However, the underlying etiology remains unclear. Our objective is to identify shared pleiotropic genetic effects and estimate the causal relationship between MS and musculoskeletal disorders. MATERIALS AND METHODS: We conducted linkage disequilibrium score regression (LDSR), colocalization, and Mendelian randomization (MR) analyses using summary statistics from recent large-scale genome-wide association studies (GWAS), encompassing MS, falls, fractures, and frailty. Additional MR analyses explored the causal relationship with musculoskeletal risk factors, such as BMD, lean mass, grip strength, and vitamin D. RESULTS: We observed a moderate genetic correlation between MS and falls (RG = 0.10, P-value = 0.01) but not between MS with fracture or frailty in the LDSR analyses. MR revealed MS had no causal association with fracture and frailty but a moderate association with falls (OR: 1.004, FDR q-value = 0.018). We further performed colocalization analyses using nine SNPs that exhibited significant associations with both MS and falls in MR. Two SNPs (rs7731626 on ANKRD55 and rs701006 on OS9 gene) showed higher posterior probability of colocalization (PP.H4 = 0.927), suggesting potential pleiotropic effects between MS and falls. The nine genes are associated with central nervous system development and inflammation signaling pathways. CONCLUSION: We found potential pleiotropic genetic effects between MS and falls. However, our analysis did not reveal a causal relationship between MS and increased risks of falls, fractures, or frailty. This suggests that the musculoskeletal disorders frequently reported in MS patients in clinical studies are more likely attributed to secondary factors associated with disease progression and treatment, rather than being directly caused by MS itself.

A genome-wide genetic association study reveals SNPs significantly associated with environmental variables and specific leaf area in European beech.

European beech is negatively affected by climate change and a further growth decline is predicted for large parts of its distribution range. Despite the importance of this species, little is known about its genetic adaptation and especially the genetic basis of its physiological traits. Here, we used genotyping by sequencing to identify SNPs in 43 German European beech populations growing under different environmental conditions. In total, 28 of these populations were located along a precipitation and temperature gradient in northern Germany, and single tree-based hydraulic and morphological traits were available. We obtained a set of 13,493 high-quality SNPs that were used for environmental and SNP-trait association analysis. In total, 22 SNPs were identified that were significantly associated with environmental variables or specific leaf area (SLA). Several SNPs were located in genes related to stress response. The majority of the significant SNPs were located in non-coding (intergenic and intronic) regions. These may be in linkage disequilibrium with the causative coding or regulatory regions. Our study gives insights into the genetic basis of abiotic adaptation in European beech, and provides genetic resources that can be used in future studies on this species. Besides clear patterns of local adaptation to environmental conditions of the investigated populations, the analyzed morphological and hydraulic traits explained most of the explainable genetic variation. Thus, they could successfully be altered in tree breeding programs, which may help to increase the adaptation of European beech to changing environmental conditions in the future.

Perturbation of the insomnia WDR90 genome-wide association studies locus pinpoints rs3752495 as a causal variant influencing distal expression of neighboring gene, PIG-Q.

Although genome-wide association studies (GWAS) have identified loci for sleep-related traits, they do not directly uncover the underlying causal variants and corresponding effector genes. The majority of such variants reside in non-coding regions and are therefore presumed to impact cis-regulatory elements. Our previously reported 'variant-to-gene mapping' effort in human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs), combined with validation in both Drosophila and zebrafish, implicated phosphatidyl inositol glycan (PIG)-Q as a functionally relevant gene at the insomnia "WDR90" GWAS locus. However, importantly that effort did not characterize the corresponding underlying causal variant. Specifically, our previous 3D genomic datasets nominated a shortlist of three neighboring single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium within an intronic enhancer region of WDR90 that contacted the open PIG-Q promoter. We sought to investigate the influence of these SNPs collectively and then individually on PIG-Q modulation to pinpoint the causal "regulatory" variant. Starting with gross level perturbation, deletion of the entire region in NPCs via CRISPR-Cas9 editing and subsequent RNA sequencing revealed expression changes in specific PIG-Q transcripts. Results from individual luciferase reporter assays for each SNP in iPSCs revealed that the region with the rs3752495 risk allele (RA) induced a ~2.5-fold increase in luciferase expression. Importantly, rs3752495 also exhibited an allele-specific effect, with the RA increasing the luciferase expression by ~2-fold versus the non-RA. In conclusion, our variant-to-function approach and in vitro validation implicate rs3752495 as a causal insomnia variant embedded within WDR90 while modulating the expression of the distally located PIG-Q.

GWAS determined genetic loci associated with callus induction in oil palm tissue culture.

KEY MESSAGE: GWAS identified six loci at 25 kb downstream of WAK2, a crucial gene for cell wall and callus formation, enabling development of a SNP marker for enhanced callus induction potential. Efficient callus induction is vital for successful oil palm tissue culture, yet identifying genomic loci and markers for early detection of genotypes with high potential of callus induction remains unclear. In this study, immature male inflorescences from 198 oil palm accessions (dura, tenera and pisifera) were used as explants for tissue culture. Callus induction rates were collected at one-, two- and three-months after inoculation (C1, C2 and C3) as phenotypes. Resequencing generated 11,475,258 high quality single nucleotide polymorphisms (SNPs) as genotypes. GWAS was then performed, and correlation analysis revealed a positive association of C1 with both C2 (R = 0.81) and C3 (R = 0.50), indicating that C1 could be used as the major phenotype for callus induction rate. Therefore, only significant SNPs (P ≤ 0.05) in C1 were identified to develop markers for screening individuals with high potential of callus induction. Among 21 significant SNPs in C1, LD block analysis revealed six SNPs on chromosome 12 (Chr12) potentially linked to callus formation. Subsequently, 13 SNP markers were identified from these loci and electrophoresis results showed that marker C-12 at locus Chr12_12704856 can be used effectively to distinguish the GG allele, which showed the highest probability (69%) of callus induction. Furthermore, a rapid SNP variant detection method without electrophoresis was established via qPCR-based melting curve analysis. Our findings facilitated marker-assisted selection for specific palms with high potential of callus induction using immature male inflorescence as explant, aiding ortet palm selection in oil palm tissue culture.

postGWAS: A web server for deciphering the causality post the genome-wide association studies.

While genome-wide association studies (GWAS) have unequivocally identified vast disease susceptibility variants, a majority of them are situated in non-coding regions and are in high linkage disequilibrium (LD). To pave the way of translating GWAS signals to clinical drug targets, it is essential to identify the underlying causal variants and further causal genes. To this end, a myriad of post-GWAS methods have been devised, each grounded in distinct principles including fine-mapping, co-localization, and transcriptome-wide association study (TWAS) techniques. Yet, no platform currently exists that seamlessly integrates these diverse post-GWAS methodologies. In this work, we present a user-friendly web server for post-GWAS analysis, that seamlessly integrates 9 distinct methods with 12 models, categorized by fine-mapping, colocalization, and TWAS. The server mainly helps users decipher the causality hindered by complex GWAS signals, including casual variants and casual genes, without the burden of computational skills and complex environment configuration, and provides a convenient platform for post-GWAS analysis, result visualization, facilitating the understanding and interpretation of the genome-wide association studies. The postGWAS server is available at http://g2g.biographml.com/.

Genome-wide classification of epigenetic activity reveals regions of enriched heritability in immune-related traits.

Epigenetics underpins the regulation of genes known to play a key role in the adaptive and innate immune system (AIIS). We developed a method, EpiNN, that leverages epigenetic data to detect AIIS-relevant genomic regions and used it to detect 2,765 putative AIIS loci. Experimental validation of one of these loci, DNMT1, provided evidence for a novel AIIS-specific transcription start site. We built a genome-wide AIIS annotation and used linkage disequilibrium (LD) score regression to test whether it predicts regional heritability using association statistics for 176 traits. We detected significant heritability effects (average |τ∗|=1.65) for 20 out of 26 immune-relevant traits. In a meta-analysis, immune-relevant traits and diseases were 4.45× more enriched for heritability than other traits. The EpiNN annotation was also depleted of trans-ancestry genetic correlation, indicating ancestry-specific effects. These results underscore the effectiveness of leveraging supervised learning algorithms and epigenetic data to detect loci implicated in specific classes of traits and diseases.

CoreSNP: an efficient pipeline for core marker profile selection from genome-wide SNP datasets in crops.

BACKGROUND: DNA marker profiles play a crucial role in the identification and registration of germplasm, as well as in the distinctness, uniformity, and stability (DUS) testing of new plant variety protection. However, selecting minimal marker sets from large-scale SNP dataset can be challenging to distinguish a maximum number of samples. RESULTS: Here, we developed the CoreSNP pipeline using a "divide and conquer" strategy and a "greedy" algorithm. The pipeline offers adjustable parameters to guarantee the distinction of each sample pair with at least two markers. Additionally, it allows datasets with missing loci as input. The pipeline was tested in barley, soybean, wheat, rice and maize. A few dozen of core SNPs were efficiently selected in different crops with SNP array, GBS, and WGS dataset, which can differentiate thousands of individual samples. The core SNPs were distributed across all chromosomes, exhibiting lower pairwise linkage disequilibrium (LD) and higher polymorphism information content (PIC) and minor allele frequencies (MAF). It was shown that both the genetic diversity of the population and the characteristics of the original dataset can significantly influence the number of core markers. In addition, the core SNPs capture a certain level of the original population structure. CONCLUSIONS: CoreSNP is an efficiency way of core marker sets selection based on Genome-wide SNP datasets of crops. Combined with low-density SNP chip or genotyping technologies, it can be a cost-effective way to simplify and expedite the evaluation of genetic resources and differentiate different crop varieties. This tool is expected to have great application prospects in the rapid comparison of germplasm and intellectual property protection of new varieties.

X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease.

BACKGROUND: Sex differences in Parkinson's disease (PD) risk are well-known. However, the role of sex chromosomes in the development and progression of PD is still unclear. OBJECTIVE: The objective of this study was to perform the first X-chromosome-wide association study for PD risk in a Latin American cohort. METHODS: We used data from three admixed cohorts: (1) Latin American Research consortium on the Genetics of Parkinson's Disease (n = 1504) as discover cohort, and (2) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (3) Bambui Aging cohort (n = 1442) as replication cohorts. We also developed an X-chromosome framework specifically designed for admixed populations. RESULTS: We identified eight linkage disequilibrium regions associated with PD. We replicated one of these regions (top variant rs525496; discovery odds ratio [95% confidence interval]: 0.60 [0.478-0.77], P = 3.13 × 10-5 replication odds ratio: 0.60 [0.37-0.98], P = 0.04). rs5525496 is associated with multiple expression quantitative trait loci in brain and non-brain tissues, including RAB9B, H2BFM, TSMB15B, and GLRA4, but colocalization analysis suggests that rs5525496 may not mediate risk by expression of these genes. We also replicated a previous X-chromosome-wide association study finding (rs28602900), showing that this variant is associated with PD in non-European populations. CONCLUSIONS: Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A weakly structured stem for human origins in Africa.

Despite broad agreement that Homo sapiens originated in Africa, considerable uncertainty surrounds specific models of divergence and migration across the continent1. Progress is hampered by a shortage of fossil and genomic data, as well as variability in previous estimates of divergence times1. Here we seek to discriminate among such models by considering linkage disequilibrium and diversity-based statistics, optimized for rapid, complex demographic inference2. We infer detailed demographic models for populations across Africa, including eastern and western representatives, and newly sequenced whole genomes from 44 Nama (Khoe-San) individuals from southern Africa. We infer a reticulated African population history in which present-day population structure dates back to Marine Isotope Stage 5. The earliest population divergence among contemporary populations occurred 120,000 to 135,000 years ago and was preceded by links between two or more weakly differentiated ancestral Homo populations connected by gene flow over hundreds of thousands of years. Such weakly structured stem models explain patterns of polymorphism that had previously been attributed to contributions from archaic hominins in Africa2-7. In contrast to models with archaic introgression, we predict that fossil remains from coexisting ancestral populations should be genetically and morphologically similar, and that only an inferred 1-4% of genetic differentiation among contemporary human populations can be attributed to genetic drift between stem populations. We show that model misspecification explains the variation in previous estimates of divergence times, and argue that studying a range of models is key to making robust inferences about deep history.

Evidence of epistasis in regions of long-range linkage disequilibrium across five complex diseases in the UK Biobank and eMERGE datasets.

Leveraging linkage disequilibrium (LD) patterns as representative of population substructure enables the discovery of additive association signals in genome-wide association studies (GWASs). Standard GWASs are well-powered to interrogate additive models; however, new approaches are required for invesigating other modes of inheritance such as dominance and epistasis. Epistasis, or non-additive interaction between genes, exists across the genome but often goes undetected because of a lack of statistical power. Furthermore, the adoption of LD pruning as customary in standard GWASs excludes detection of sites that are in LD but might underlie the genetic architecture of complex traits. We hypothesize that uncovering long-range interactions between loci with strong LD due to epistatic selection can elucidate genetic mechanisms underlying common diseases. To investigate this hypothesis, we tested for associations between 23 common diseases and 5,625,845 epistatic SNP-SNP pairs (determined by Ohta's D statistics) in long-range LD (>0.25 cM). Across five disease phenotypes, we identified one significant and four near-significant associations that replicated in two large genotype-phenotype datasets (UK Biobank and eMERGE). The genes that were most likely involved in the replicated associations were (1) members of highly conserved gene families with complex roles in multiple pathways, (2) essential genes, and/or (3) genes that were associated in the literature with complex traits that display variable expressivity. These results support the highly pleiotropic and conserved nature of variants in long-range LD under epistatic selection. Our work supports the hypothesis that epistatic interactions regulate diverse clinical mechanisms and might especially be driving factors in conditions with a wide range of phenotypic outcomes.

Interchromosomal linkage disequilibrium and linked fitness cost loci associated with selection for herbicide resistance.

The adaptation of weeds to herbicide is both a significant problem in agriculture and a model of rapid adaptation. However, significant gaps remain in our knowledge of resistance controlled by many loci and the evolutionary factors that influence the maintenance of resistance. Here, using herbicide-resistant populations of the common morning glory (Ipomoea purpurea), we perform a multilevel analysis of the genome and transcriptome to uncover putative loci involved in nontarget-site herbicide resistance (NTSR) and to examine evolutionary forces underlying the maintenance of resistance in natural populations. We found loci involved in herbicide detoxification and stress sensing to be under selection and confirmed that detoxification is responsible for glyphosate (RoundUp) resistance using a functional assay. We identified interchromosomal linkage disequilibrium (ILD) among loci under selection reflecting either historical processes or additive effects leading to the resistance phenotype. We further identified potential fitness cost loci that were strongly linked to resistance alleles, indicating the role of genetic hitchhiking in maintaining the cost. Overall, our work suggests that NTSR glyphosate resistance in I. purpurea is conferred by multiple genes which are potentially maintained through generations via ILD, and that the fitness cost associated with resistance in this species is likely a by-product of genetic hitchhiking.

Association between the ELAVL1 gene single nucleotide polymorphisms and the Genetic Susceptibility to cervical cancer by high resolution melting in a Tunisian population.

BACKGROUND: Human papillomavirus is the major cause of cervical cancer, but only few cases develop into cancer. Nevertheless, HuR (ELAVL1) gene has been implicated in the oncogenesis of certain cancers. The correlation between ELAVL1 gene and the risk of cervical cancer remains unclear. Therefore, this study investigated the effect of ELAVL1 gene polymorphisms (SNPs) in cervical cancer development in Tunisian women. METHOD: ELAVL1 gene SNPs: ELAVL1 rs12983784 T > C, ELAVL1 rs14394 T > C, ELAVL1 rs74369359 G > T, ELAVL1 rs35986520 G > A, ELAVL1 rs10402477 C > T, ELAVL1 rs12985234 A > G and ELAVL1 rs2042920 T > G, were genotyped by High resolution melting (HRM). SNPStats software was used to perform linkage disequilibrium (LD) and haplotype analysis. RESULTS: Comparing the cervical cancer patients with healthy control participants, the SNPs rs12983784 (P = 0.032), rs74369359 (p = < 10- 3) and rs10402477 (P = 0.001) were associated with an increased cervical cancer risk. Contrary to the SNPs rs14394, rs7469359, rs35986520, rs12985234 and rs2042920 (p˃0.05). The haplotype analysis of the seven SNPs of ELAVL1 gene showed that there is no association between the different haplotypes and a possible risk of cervical cancer disease. Moreover, there was a significant Linkage disequilibrium between rs35986520 and rs2042920 (D'=0.9972) and between rs2042920 and rs10402477 (D'=0.9977). CONCLUSION: Our results indicated that genetic variants in the ELAVL1 gene might be associated with susceptibility to cervical cancer in the Tunisian population.

An overview of genome-wide association mapping studies in Poaceae species (model crops: wheat and rice).

There is a significant interest while utilizing association mapping technique to determine the genes which are accountable for numerical dissimilarity of the more complex characteristics with agronomic and evolutionary significance. Recently improvements have been made in genomic technology, which motivates for the exploitation of natural diversity, and establishment of more vigorous and strong statistical analysis methods. It creates association mapping technique more demanding and reasonable to plant research programs. Genome-wide association mapping technique recognizes quantitative trait loci (QTLs) by studying the marker-trait associations which could be credited to the power of linkage disequilibrium between different molecular markers and functional polymorphisms through a pool of diversified germplasm. In this review, we will describe an overview of genetic mapping and the current status of association mapping studies in model cereal crops i.e., wheat and rice.

A saturated map of common genetic variants associated with human height.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

The evolutionary patterns of barley pericentromeric chromosome regions, as shaped by linkage disequilibrium and domestication.

The distribution of recombination events along large cereal chromosomes is uneven and is generally restricted to gene-rich telomeric ends. To understand how the lack of recombination affects diversity in the large pericentromeric regions, we analysed deep exome capture data from a final panel of 815 Hordeum vulgare (barley) cultivars, landraces and wild barleys, sampled from across their eco-geographical ranges. We defined and compared variant data across the pericentromeric and non-pericentromeric regions, observing a clear partitioning of diversity both within and between chromosomes and germplasm groups. Dramatically reduced diversity was found in the pericentromeres of both cultivars and landraces when compared with wild barley. We observed a mixture of completely and partially differentiated single-nucleotide polymorphisms (SNPs) between domesticated and wild gene pools, suggesting that domesticated gene pools were derived from multiple wild ancestors. Patterns of genome-wide linkage disequilibrium, haplotype block size and number, and variant frequency within blocks showed clear contrasts among individual chromosomes and between cultivars and wild barleys. Although most cultivar chromosomes shared a single major pericentromeric haplotype, chromosome 7H clearly differentiated the two-row and six-row types associated with different geographical origins. Within the pericentromeric regions we identified 22 387 non-synonymous SNPs, 92 of which were fixed for alternative alleles in cultivar versus wild accessions. Surprisingly, only 29 SNPs found exclusively in the cultivars were predicted to be 'highly deleterious'. Overall, our data reveal an unconventional pericentromeric genetic landscape among distinct barley gene pools, with different evolutionary processes driving domestication and diversification.

Functional characterization of the schizophrenia associated gene AS3MT identifies a role in neuronal development.

Genome-wide association studies (GWAS) have identified multiple genomic regions associated with schizophrenia, although many variants reside in noncoding regions characterized by high linkage disequilibrium (LD) making the elucidation of molecular mechanisms challenging. A genomic region on chromosome 10q24 has been consistently associated with schizophrenia with risk attributed to the AS3MT gene. Although AS3MT is hypothesized to play a role in neuronal development and differentiation, work to fully understand the function of this gene has been limited. In this study we explored the function of AS3MT using a neuronal cell line (SH-SY5Y). We confirm previous findings of isoform specific expression of AS3MT during SH-SY5Y differentiation toward neuronal fates. Using CRISPR-Cas9 gene editing we generated AS3MT knockout SH-SY5Y cell lines and used RNA-seq to identify significant changes in gene expression in pathways associated with neuronal development, inflammation, extracellular matrix formation, and RNA processing, including dysregulation of other genes strongly implicated in schizophrenia. We did not observe any morphological changes in cell size and neurite length following neuronal differentiation and MAP2 immunocytochemistry. These results provide novel insights into the potential role of AS3MT in brain development and identify pathways through which genetic variation in this region may confer risk for schizophrenia.