Candidate Causal Variants Research Articles

Cardiac cell type-specific gene regulatory programs and disease risk association.

Misregulated gene expression in human hearts can result in cardiovascular diseases that are leading causes of mortality worldwide. However, the limited information on the genomic location of candidate cis-regulatory elements (cCREs) such as enhancers and promoters in distinct cardiac cell types has restricted the understanding of these diseases. Here, we defined >287,000 cCREs in the four chambers of the human heart at single-cell resolution, which revealed cCREs and candidate transcription factors associated with cardiac cell types in a region-dependent manner and during heart failure. We further found cardiovascular disease-associated genetic variants enriched within these cCREs including 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. Additional functional studies revealed that two of these variants affect a cCRE controlling KCNH2/HERG expression and action potential repolarization. Overall, this atlas of human cardiac cCREs provides the foundation for illuminating cell type-specific gene regulation in human hearts during health and disease.

Autosomal recessive loci contribute significantly to quantitative variation of male fertility in a dairy cattle population

BackgroundCattle are ideally suited to investigate the genetics of male fertility. Semen from individual bulls is used for thousands of artificial inseminations for which the fertilization success is monitored. Results from the breeding soundness examination and repeated observations of semen quality complement the fertility evaluation for each bull.ResultsIn a cohort of 3881 Brown Swiss bulls that had genotypes at 683,609 SNPs, we reveal four novel recessive QTL for male fertility on BTA1, 18, 25, and 26 using haplotype-based association testing. A QTL for bull fertility on BTA1 is also associated with sperm head shape anomalies. All other QTL are not associated with any of the semen quality traits investigated. We perform complementary fine-mapping approaches using publicly available transcriptomes as well as whole-genome sequencing data of 125 Brown Swiss bulls to reveal candidate causal variants. We show that missense or nonsense variants in SPATA16, VWA3A, ENSBTAG00000006717 and ENSBTAG00000019919 are in linkage disequilibrium with the QTL. Using whole-genome sequence data, we detect strong association (P = 4.83 × 10− 12) of a missense variant (p.Ile193Met) in SPATA16 with male fertility. However, non-coding variants exhibit stronger association at all QTL suggesting that variants in regulatory regions contribute to variation in bull fertility.ConclusionOur findings in a dairy cattle population provide evidence that recessive variants may contribute substantially to quantitative variation in male fertility in mammals. Detecting causal variants that underpin variation in male fertility remains difficult because the most strongly associated variants reside in poorly annotated non-coding regions.

The role of clinical response to treatment in determining pathogenicity of genomic variants

The 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants provide a framework to standardize terminology in the classification of variants uncovered through genetic testing. We aimed to assess the validity of utilizing clinical response to therapies specifically targeted to a suspected disease in clarifying variant pathogenicity. Five families with disparate clinical presentations and different genetic diseases evaluated and treated in multiple diagnostic settings are summarized. Extended evaluations indicated possible genetic diagnoses and assigned candidate causal variants, but the cumulative clinical, biochemical, and molecular information in each instance was not completely consistent with the identified disease. Initiation of treatment specific to the suspected diagnoses in the affected individuals led to clinical improvement in all five families. We propose that the effect of therapies that are specific and targeted to treatable genetic diseases embodies an in vivo physiological response and could be considered as additional criteria within the 2015 ACMG/AMP guidelines in determining genomic variant pathogenicity.

Whole-genome sequence diversity and association analysis of 198 soybean accessions in mini-core collections.

We performed whole-genome Illumina resequencing of 198 accessions to examine the genetic diversity and facilitate the use of soybean genetic resources and identified 10 million single nucleotide polymorphisms and 2.8 million small indels. Furthermore, PacBio resequencing of 10 accessions was performed, and a total of 2,033 structure variants were identified. Genetic diversity and structure analysis congregated the 198 accessions into three subgroups (Primitive, World, and Japan) and showed the possibility of a long and relatively isolated history of cultivated soybean in Japan. Additionally, the skewed regional distribution of variants in the genome, such as higher structural variations on the R gene clusters in the Japan group, suggested the possibility of selective sweeps during domestication or breeding. A genome-wide association study identified both known and novel causal variants on the genes controlling the flowering period. Novel candidate causal variants were also found on genes related to the seed coat colour by aligning together with Illumina and PacBio reads. The genomic sequences and variants obtained in this study have immense potential to provide information for soybean breeding and genetic studies that may uncover novel alleles or genes involved in agronomically important traits.

A COL7A1 Variant in a Litter of Neonatal Basset Hounds with Dystrophic Epidermolysis Bullosa.

We investigated three neonatal Basset Hound littermates with lesions consistent with epidermolysis bullosa (EB), a group of genetic blistering diseases. A clinically normal bitch was bred to her grandfather by artificial insemination. Out of a litter of seven puppies, two affected puppies died and one was euthanized, with these puppies being submitted for diagnostic necropsy. All had multiple bullae and ulcers involving the nasal planum and paw pads, as well as sloughing claws; one puppy also had oral and esophageal ulcers. The complete genome of one affected puppy was sequenced, and 37 known EB candidate genes were assessed. We found a candidate causative variant in COL7A1, which encodes the collagen VII alpha 1 chain. The variant is a complex rearrangement involving duplication of a 107 bp region harboring a frameshift deletion of 7 bp. The variant is predicted to truncate more than 75% of the open reading frame, p.(Val677Serfs*11). Targeted genotyping of this duplication confirmed that all three affected puppies were homozygous for the duplication, whereas 12 unaffected Basset Hounds did not carry the duplication. This variant was also not seen in the genomes of more than 600 dogs of other breeds. COL7A1 variants have been identified in humans and dogs with dystrophic epidermolysis bullosa (DEB). The identified COL7A1 variant therefore most likely represents the causative variant and allows the refinement of the preliminary EB diagnosis to DEB.

Fine-mapping and cell-specific enrichment at corneal resistance factor loci prioritize candidate causal regulatory variants

Corneal resistance factor (CRF) is altered during corneal diseases progression. Genome-wide-association studies (GWAS) indicated potential CRF and disease genetics overlap. Here, we characterise 135 CRF loci following GWAS in 76029 UK Biobank participants. Enrichment of extra-cellular matrix gene-sets, genetic correlation with corneal thickness (70% (SE = 5%)), reported keratoconus risk variants at 13 loci, all support relevance to corneal stroma biology. Fine-mapping identifies a subset of 55 highly likely causal variants, 91% of which are non-coding. Genomic features enrichments, using all associated variants, also indicate prominent regulatory causal role. We newly established open chromatin landscapes in two widely-used human cornea immortalised cell lines using ATAC-seq. Variants associated with CRF were significantly enriched in regulatory regions from the corneal stroma-derived cell line and enrichment increases to over 5 fold for variants prioritised by fine-mapping-including at GAS7, SMAD3 and COL6A1 loci. Our analysis generates many hypotheses for future functional validation of aetiological mechanisms.

Abstract 13435: Characterization of Open Chromatin in Human Mitral Valves to Identify Regulatory Mechanisms at Mitral Valve Prolapse Genetic Loci

Introduction: Mitral valve prolapse (MVP) is a common valve disease that leads to mitral insufficiency, heart failure, and sudden death. The identification of genetic risk loci provided insight into its genetic architecture, although the causal variants and target genes need to be fully characterized. Hypothesis: Functional genomic annotation, including chromatin accessibility profiles of human mitral valves, allows the characterization of variants and target genes at MVP loci. Methods: We determined open chromatin regions using the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) from surgically removed human valves and primary cultures of fibroblasts. We analyzed the spatial conformation of MVP-associated loci using circular chromatin conformation capture (4C-Seq) with candidate causal variants as viewpoints. Candidate causal variants were followed-up using reporter assays and in silico analyses. Results: We mapped the open chromatin from 11 human mitral valves and 3 primary cell cultures. We found that mitral valve-specific ATAC-Seq peaks were enriched near genes involved in extracellular matrix organization, chondrocyte differentiation, and connective tissue development. We also found that MVP-associated variants (p<10 -5 ) observed in the MVP GWAS were significantly enriched (p<0.05) in mitral valve open chromatin regions, but not in heart tissue from ENCODE. We found that rs6723013 on Chr2 belongs to a valve-specific enhancer at the IGFBP5/TNS1 locus and is the most likely causal variant at this locus. We also identified several plausible causal SNPs and, by using 4C-Seq, potential target genes ( HIC1 and DPH1 ) at the SMG6/SRR locus. Conclusions: Here we describe unprecedented genome-wide open chromatin profiles from human mitral valves that indicate specific gene regulation profiles, compared to the heart. We also report in vitro functional evidence for potential causal variants and target genes at MVP risk loci involving established and new biological mechanisms relevant to mitral valve disease.

A Novel IRF6 Variant Detected in a Family With Nonsyndromic Cleft Lip and Palate by Whole Exome Sequencing.

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common congenital craniofacial malformation, and its harmful effects on affected individuals and families are apparent. The causative genes and their mechanisms are not completely clear, although several studies have been conducted. Accordingly, in the present study, we recruited a Han Chinese family with hereditary NSCL/P to explore the possible causative variants of this disease using whole exome sequencing. Bioinformatics screening and analysis, mutation function prediction, species conservation analysis, and homology protein modeling were used to identify the variants and evaluate their influence. A mutation in the interferon regulatory factor 6 (IRF6) gene (c.961C>T; p.Val321Met) was detected as a candidate causative variant and predicted to be deleterious. The codon was found to be conserved in many species, and the residue change caused by this mutation changed the structure of IRF6 to a certain degree. The findings suggest that this IRF6 variant is probably the pathogenic cause of NSCL/P in this family. Our results further provide evidence that IRF6 variants play a role in the etiology of NSCL/P.

Single-cell epigenomic analyses implicate candidate causal variants at inherited risk loci for Alzheimer's and Parkinson's diseases.

Genome-wide association studies (GWAS) of neurological diseases have identified thousands of variants associated with disease phenotypes. However, the majority of these variants do not alter coding sequences, making it difficult to assign their function. Here, we present a multi-omic epigenetic atlas of the adult human brain through profiling of single-cell chromatin accessibility landscapes and three-dimensional (3D) chromatin interactions of diverse adult brain regions across a cohort of cognitively healthy individuals. We developed a machine-learning classifier to integrate this multi-omic framework and predict dozens of functional single-nucleotide polymorphisms (SNPs) for Alzheimer’s disease (AD) and Parkinson’s disease (PD), nominating target genes and cell types for previously orphaned GWAS loci. Moreover, we dissected the complex inverted haplotype of the MAPT (encoding tau) PD risk locus, identifying putative ectopic regulatory interactions in neurons that may mediate this disease association. This work expands our understanding of inherited variation and provides a roadmap for the epigenomic dissection of causal regulatory variation in disease.

Genomic diversity and population structure of the Leonberger dog breed

BackgroundLeonberger is a giant dog breed formed in the 1850s in Germany. Its post-World War II popularity has resulted in a current global population of ~ 30,000 dogs. The breed has predispositions to neurodegenerative disorders and cancer, which is likely due in large part to limited genetic diversity. However, to date there is no scientific literature on the overall demography and genomic architecture of this breed.ResultsWe assessed extensive pedigree records, SNP array genotype data, and whole-genome sequences (WGS) on 142,072, 1203 and 39 Leonberger dogs, respectively. Pedigree analyses identified 22 founder animals and revealed an apparent popular sire effect. The average pedigree-based inbreeding coefficient of 0.29 and average kinship of 0.31 show a dramatic loss of genetic diversity. The observed average life span decreased over time from 9.4 years in 1989 to 7.7 years in 2004. A global health survey confirmed a high prevalence of cancer and neurological disorders. Analysis of SNP-based runs of homozygosity (ROH) identified 125,653 ROH with an average length of 5.88 Mb, and confirmed an average inbreeding coefficient of 0.28. Genome-wide filtering of the WGS data revealed 28 non-protein-changing variants that were present in all Leonberger individuals and a list of 22 potentially pathogenic variants for neurological disorders of which 50% occurred only in Leonbergers and 50% occurred rarely in other breeds. Furthermore, one of the two mtDNA haplogroups detected was present in one dog only.ConclusionsThe increasing size of the Leonberger population has been accompanied by a considerable loss of genetic diversity after the bottleneck that occurred in the 1940s due to the intensive use of popular sires resulting in high levels of inbreeding. This might explain the high prevalence of certain disorders; however, genomic data provide no evidence for fixed coding variants that explain these predispositions. The list of candidate causative variants for polyneuropathy needs to be further evaluated. Preserving the current genetic diversity is possible by increasing the number of individuals for breeding while restricting the number of litters per sire/dam. In addition, outcrossing would help optimize long-term genetic diversity and contribute to the sustainability and health of the population.

An integrated peach genome structural variation map uncovers genes associated with fruit traits

BackgroundGenome structural variations (SVs) have been associated with key traits in a wide range of agronomically important species; however, SV profiles of peach and their functional impacts remain largely unexplored.ResultsHere, we present an integrated map of 202,273 SVs from 336 peach genomes. A substantial number of SVs have been selected during peach domestication and improvement, which together affect 2268 genes. Genome-wide association studies of 26 agronomic traits using these SVs identify a number of candidate causal variants. A 9-bp insertion in Prupe.4G186800, which encodes a NAC transcription factor, is shown to be associated with early fruit maturity, and a 487-bp deletion in the promoter of PpMYB10.1 is associated with flesh color around the stone. In addition, a 1.67 Mb inversion is highly associated with fruit shape, and a gene adjacent to the inversion breakpoint, PpOFP1, regulates flat shape formation.ConclusionsThe integrated peach SV map and the identified candidate genes and variants represent valuable resources for future genomic research and breeding in peach.

A Novel Variant in CWF19L1 Gene in a Family with Late-Onset Autosomal Recessive Cerebellar Ataxia 17

ABSTRACT Introduction Previously published studies demonstrated that mutations in CWF19L1 cause early-onset autosomal recessive cerebellar ataxia 17. In this article, we report a novel homozygous missense variant in CWF19L1 in two sisters who had late-onset cerebellar ataxia with epilepsy and describe their clinical and neuroradiological findings. Methods We included two female patients with typical symptoms of cerebellar ataxia supported by the MRI findings. Whole exome sequencing (WES) data analysis was performed to identify the underlying genetic defect in the proband. Sanger sequencing was used to confirm the variant in other family members. Results WES revealed a homozygous missense variant in CWF19-like protein 1; CWF19L1 gene c.395A>G; p.(Asp132Gly) (RefSeq NM_018294.4). This variant has not been described previously in the literature. Mutations in this gene are known to cause an autosomal recessive disorder, spinocerebellar ataxia, autosomal recessive 17 (OMIM #616127). Conclusion In conclusion, we report a novel variant in CWF19L1 as a candidate causal variant in two sisters with autosomal recessive cerebellar ataxia. This is the first report coming from Arab countries. Additional reports in patients with a progressive course and adult-onset are needed, but this could be the first report of this disease diagnosed in adulthood since it is a disease of children and adolescents. In addition, our patients had epileptic seizures, which were not previously documented in patients with CWF19L1 mutations. We postulate that mutations in this gene have widespread functional and structural changes in multiple levels of the neuraxis rather than being a pure cerebellar disorder.

Ovarian Cancer Risk Variants Are Enriched in Histotype-Specific Enhancers and Disrupt Transcription Factor Binding Sites

Quantifying the functional effects of complex disease risk variants can provide insights into mechanisms underlying disease biology. Genome-wide association studies have identified 39 regions associated with risk of epithelial ovarian cancer (EOC). The vast majority of these variants lie in the non-coding genome, where they likely function through interaction with gene regulatory elements. In this study we first estimated the heritability explained by known common low penetrance risk alleles for EOC. The narrow sense heritability (hg2) of EOC overall and high-grade serous ovarian cancer (HGSOCs) were estimated to be 5%-6%. Partitioned SNP heritability across broad functional categories indicated a significant contribution of regulatory elements to EOC heritability. We collated epigenomic profiling data for 77 cell and tissue types from Roadmap Epigenomics and ENCODE, and from H3K27Ac ChIP-seq data generated in 26 ovarian cancer and precursor-related cell and tissue types. We identified significant enrichment of risk single-nucleotide polymorphisms (SNPs) in active regulatory elements marked by H3K27Ac in HGSOCs. To further investigate how risk SNPs in active regulatory elements influence predisposition to ovarian cancer, we used motifbreakR to predict the disruption of transcription factor binding sites. We identified 469 candidate causal risk variants in H3K27Ac peaks that are predicted to significantly break transcription factor (TF) motifs. The most frequently broken motif was REST (p value = 0.0028), which has been reported as both a tumor suppressor and an oncogene. Overall, these systematic functional annotations with epigenomic data improve interpretation of EOC risk variants and shed light on likely cells of origin.

Genome-wide landscape establishes novel association signals for metabolic traits in the Arab population

While the Arabian population has a high prevalence of metabolic disorders, it has not been included in global studies that identify genetic risk loci for metabolic traits. Determining the transferability of such largely Euro-centric established risk loci is essential to transfer the research tools/resources, and drug targets generated by global studies to a broad range of ethnic populations. Further, consideration of populations such as Arabs, that are characterized by consanguinity and a high level of inbreeding, can lead to identification of novel risk loci. We imputed published GWAS data from two Kuwaiti Arab cohorts (n = 1434 and 1298) to the 1000 Genomes Project haplotypes and performed meta-analysis for associations with 13 metabolic traits. We compared the observed association signals with those established for metabolic traits. Our study highlighted 70 variants from 9 different genes, some of which have established links to metabolic disorders. By relaxing the genome-wide significance threshold, we identified ‘novel’ risk variants from 11 genes for metabolic traits. Many novel risk variant association signals were observed at or borderline to genome-wide significance. Furthermore, 349 previously established variants from 187 genes were validated in our study. Pleiotropic effect of risk variants on multiple metabolic traits were observed. Fine-mapping illuminated rs7838666/CSMD1 rs1864163/CETP and rs112861901/[INTS10,LPL] as candidate causal variants influencing fasting plasma glucose and high-density lipoprotein levels. Computational functional analysis identified a variety of gene regulatory signals around several variants. This study enlarges the population ancestry diversity of available GWAS and elucidates new variants in an ethnic group burdened with metabolic disorders.

Ear type in sheep is associated with the MSRB3 locus

Ear morphology is an important determinant of sheep breeds. It includes different variable traits such as ear size and erectness, suggesting a polygenic architecture. Here, we performed a comprehensive genome-wide analysis to identify regions under selection for ear morphology in 515 sheep from 17 breeds fixed for diverse ear phenotypes using 34k SNP genotyping data. GWASs for two ear type traits, size and erectness, revealed a single genome-wide significant association on ovine chromosome 3. The derived marker alleles were enriched in sheep with large and/or floppy ears. The GWAS signal harboured the MSRB3 gene encoding methionine sulphoxide reductase B3, which has already been found to be associated with different ear types in other species. We attempted whole-genome resequencing to identify causal variant(s) within a 1Mb interval around MSRB3. This experiment excluded major copy number variants in the interval, but failed to identify a compelling candidate causal variant. Fine-mapping suggested that the causal variant for large floppy ears most likely resides in a 175kb interval downstream of the MSRB3 coding region.

Abstract 3513: Genome-wide scan for novel prostate cancer susceptibility loci with clinical consequence utilizing increased genetic drift of the Finnish population

Abstract Background: Prostate cancer (PC) is the second most common cancer in men worldwide with a rising prevalence. However, only limited number of clinically actionable variants are known. The objective of this study is to identify novel PC susceptibility loci with potential clinical relevance utilizing the increased genetic drift and reduced selective pressure of the recently bottlenecked powerful resource of the Finnish population. Methods: We meta-analysed >185.000 germline single nucleotide polymorphisms (SNPs) in 2738 PC cases and 2401 controls of Finnish origin in the Collaborative Oncological Gene-Environment Study (COGS) using Illumina iSelect custom SNP genotyping platform. Results: Altogether 160 variants remain significant on GWAS level (p<5 × 10−8) in 18 different gene regions. Out of the 160 identified PC susceptibility hits 78 (49%) are novel variants not reported earlier in association with PC. PC associated signals are in close proximity to one another forming genetic hot-spots on chromosomes 8, 7, 11, 17 and 19. The strength of association varies for 101 PC risk variants (OR 1.24-1.86) and 59 protective SNPs (OR 0.59-0.80). The strongest risk gene is CASC8 (OR=1.86; p=1.214 × 10−11). The most significant signals were found at the 8p21.2 chromosomal region (p<7.6 × 10−16). Functional annotation identified a missense coding SNP at KLK3 gene to be a candidate causal variant. We showed evidence for association both with early-onset PC (OR 1.73; P=0.02), high serum PSA level at diagnosis (OR 1.36; P=0.024) and with aggressive PC (Gleason score ≥8; OR 1.44; P=0.02) at 17q21. Conclusion: The results facilitate risk stratification for screening, clinical studies, treatment choices and functional research of PC Citation Format: Csilla Sipeky, Teuvo L. Tammela, Anssi Auvinen, Johanna Schleutker. Genome-wide scan for novel prostate cancer susceptibility loci with clinical consequence utilizing increased genetic drift of the Finnish population [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3513.

Trans-ancestral dissection of urate- and gout-associated major loci SLC2A9 and ABCG2 reveals primate-specific regulatory effects.

Gout is a complex inflammatory arthritis affecting ~20% of people with an elevated serum urate level (hyperuricemia). Gout and hyperuricemia are essentially specific to humans and other higher primates, with varied prevalence across ancestral groups. SLC2A9 and ABCG2 are major loci associated with both urate and gout in multiple ancestral groups. However, fine mapping has been challenging due to extensive linkage disequilibrium underlying the associated regions. We used trans-ancestral fine mapping integrated with primate-specific genomic information to address this challenge. Trans-ancestral meta-analyses of GWAS cohorts of either European (EUR) or East Asian (EAS) ancestry resulted in single-variant resolution mappings for SLC2A9 (rs3775948 for urate and rs4697701 for gout) and ABCG2 (rs2622621 for gout). Tests of colocalization of variants in both urate and gout suggested existence of a shared candidate causal variant for SLC2A9 only in EUR and for ABCG2 only in EAS. The fine-mapped gout variant rs4697701 was within an ancient enhancer, whereas rs2622621 was within a primate-specific transposable element, both supported by functional evidence from the Roadmap Epigenomics project in human primary tissues relevant to urate and gout. Additional primate-specific elements were found near both loci and those adjacent to SLC2A9 overlapped with known statistical epistatic interactions associated with urate as well as multiple super-enhancers identified in urate-relevant tissues. We conclude that by leveraging ancestral differences trans-ancestral fine mapping has identified ancestral and functional variants for SLC2A9 or ABCG2 with primate-specific regulatory effects on urate and gout.

Mitochondrial PCK2 Missense Variant in Shetland Sheepdogs with Paroxysmal Exercise-Induced Dyskinesia (PED).

Four female Shetland Sheepdogs with hypertonic paroxysmal dyskinesia, mainly triggered by exercise and stress, were investigated in a retrospective multi-center investigation aiming to characterize the clinical phenotype and its underlying molecular etiology. Three dogs were closely related and their pedigree suggested autosomal dominant inheritance. Laboratory diagnostic findings included mild lactic acidosis and lactaturia, mild intermittent serum creatine kinase (CK) elevation and hypoglycemia. Electrophysiological tests and magnetic resonance imaging of the brain were unremarkable. A muscle/nerve biopsy revealed a mild type II fiber predominant muscle atrophy. While treatment with phenobarbital, diazepam or levetiracetam did not alter the clinical course, treatment with a gluten-free, home-made fresh meat diet in three dogs or a tryptophan-rich, gluten-free, seafood-based diet, stress-reduction, and acetazolamide or zonisamide in the fourth dog correlated with a partial reduction in, or even a complete absence of, dystonic episodes. The genomes of two cases were sequenced and compared to 654 control genomes. The analysis revealed a case-specific missense variant, c.1658G>A or p.Arg553Gln, in the PCK2 gene encoding the mitochondrial phosphoenolpyruvate carboxykinase 2. Sanger sequencing confirmed that all four cases carried the mutant allele in a heterozygous state. The mutant allele was not found in 117 Shetland Sheepdog controls and more than 500 additionally genotyped dogs from various other breeds. The p.Arg553Gln substitution affects a highly conserved residue in close proximity to the GTP-binding site of PCK2. Taken together, we describe a new form of paroxysmal exercise-induced dyskinesia (PED) in dogs. The genetic findings suggest that PCK2:p.Arg553Gln should be further investigated as putative candidate causal variant.

Werewolf, There Wolf: Variants in Hairless Associated with Hypotrichia and Roaning in the Lykoi Cat Breed.

A variety of cat breeds have been developed via novelty selection on aesthetic, dermatological traits, such as coat colors and fur types. A recently developed breed, the lykoi (a.k.a. werewolf cat), was bred from cats with a sparse hair coat with roaning, implying full color and all white hairs. The lykoi phenotype is a form of hypotrichia, presenting as a significant reduction in the average numbers of follicles per hair follicle group as compared to domestic shorthair cats, a mild to severe perifollicular to mural lymphocytic infiltration in 77% of observed hair follicle groups, and the follicles are often miniaturized, dilated, and dysplastic. Whole genome sequencing was conducted on a single lykoi cat that was a cross between two independently ascertained lineages. Comparison to the 99 Lives dataset of 194 non-lykoi cats suggested two variants in the cat homolog for Hairless (HR) (HR lysine demethylase and nuclear receptor corepressor) as candidate causal gene variants. The lykoi cat was a compound heterozygote for two loss of function variants in HR, an exon 3 c.1255_1256dupGT (chrB1:36040783), which should produce a stop codon at amino acid 420 (p.Gln420Serfs*100) and, an exon 18 c.3389insGACA (chrB1:36051555), which should produce a stop codon at amino acid position 1130 (p.Ser1130Argfs*29). Ascertainment of 14 additional cats from founder lineages from Canada, France and different areas of the USA identified four additional loss of function HR variants likely causing the highly similar phenotypic hair coat across the diverse cats. The novel variants in HR for cat hypotrichia can now be established between minor differences in the phenotypic presentations.

Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10-9). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.