Genome-Wide Association Study of NAFLD Using Electronic Health Records.

Genome-wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta-analysis using available summary association statistics. Six risk loci were identified (P < 5*10-8 ) (apolipoprotein E [APOE], patatin-like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta-analysis. Rs429358 (P = 2.17*10-11 ) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusion: This GWAS replicates six known NAFLD-susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches.

Genome-wide analysis identifies gallstone-susceptibility loci including genes regulating gastrointestinal motility.

BACKGROUND AND AIMS: Genome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely that many genetic determinants are undiscovered. The aim of this study was to identify genetic variants that represent new targets for gallstone research and treatment. APPROACH AND RESULTS: We performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1089 cases, 5228 controls), and conducted a GWA meta-analysis (43,639 cases, 506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of identified genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy-five risk loci were identified (p < 5 × 10-8 ), of which 46 were new. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism, and gastrointestinal motility. Anoctamin 1 (ANO1) and transmembrane Protein 147 (TMEM147), both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599-A leads to suppression of hepatic TMEM147 expression, suggesting that the protein protects against gallstone formation. The highest decile of the PRS demonstrated a 6-fold increased odds of gallstones compared with the lowest decile. The PRS was strongly associated with increased body mass index, serum liver enzymes, and C-reactive protein concentrations, and decreased lipoprotein cholesterol concentrations. CONCLUSIONS: This GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. We implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.

Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease.

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

Autozygosity influences cardiometabolic disease-associated traits in the AWI-Gen sub-Saharan African study.

The analysis of the effects of autozygosity, measured as the change of the mean value of a trait among offspring of genetic relatives, reveals the existence of directional dominance or overdominance. In this study we detect evidence of the effect of autozygosity in 4 out of 13 cardiometabolic disease-associated traits using data from more than 10,000 sub-Saharan African individuals recruited from Ghana, Burkina Faso, Kenya and South Africa. The effect of autozygosity on these phenotypes is found to be sex-related, with inbreeding having a significant decreasing effect in men but a significant increasing effect in women for several traits (body mass index, subcutaneous adipose tissue, low-density lipoproteins and total cholesterol levels). Overall, the effect of inbreeding depression is more intense in men. Differential effects of inbreeding depression are also observed between study sites with different night-light intensity used as proxy for urban development. These results suggest a directional dominant genetic component mediated by environmental interactions and sex-specific differences in genetic architecture for these traits in the Africa Wits-INDEPTH partnership for Genomic Studies (AWI-Gen) cohort.

Linking protein to phenotype with Mendelian Randomization detects 38 proteins with causal roles in human diseases and traits.

To efficiently transform genetic associations into drug targets requires evidence that a particular gene, and its encoded protein, contribute causally to a disease. To achieve this, we employ a three-step proteome-by-phenome Mendelian Randomization (MR) approach. In step one, 154 protein quantitative trait loci (pQTLs) were identified and independently replicated. From these pQTLs, 64 replicated locally-acting variants were used as instrumental variables for proteome-by-phenome MR across 846 traits (step two). When its assumptions are met, proteome-by-phenome MR, is equivalent to simultaneously running many randomized controlled trials. Step 2 yielded 38 proteins that significantly predicted variation in traits and diseases in 509 instances. Step 3 revealed that amongst the 271 instances from GeneAtlas (UK Biobank), 77 showed little evidence of pleiotropy (HEIDI), and 92 evidence of colocalization (eCAVIAR). Results were wide ranging: including, for example, new evidence for a causal role of tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS1; SIRPA) in schizophrenia, and a new finding that intestinal fatty acid binding protein (FABP2) abundance contributes to the pathogenesis of cardiovascular disease. We also demonstrated confirmatory evidence for the causal role of four further proteins (FGF5, IL6R, LPL, LTA) in cardiovascular disease risk.

The multifunctional protein PACS-1 is required for HDAC2- and HDAC3-dependent chromatin maturation and genomic stability.

Phosphofurin acidic cluster sorting protein-1 (PACS-1) is a multifunctional membrane traffic regulator that plays important roles in organ homeostasis and disease. In this study, we elucidate a novel nuclear function for PACS-1 in maintaining chromosomal integrity. PACS-1 progressively accumulates in the nucleus during cell cycle progression, where it interacts with class I histone deacetylases 2 and 3 (HDAC2 and HDAC3) to regulate chromatin dynamics by maintaining the acetylation status of histones. PACS-1 knockdown results in the proteasome-mediated degradation of HDAC2 and HDAC3, compromised chromatin maturation, as indicated by elevated levels of histones H3K9 and H4K16 acetylation, and, consequently, increased replication stress-induced DNA damage and genomic instability.

Associations of autozygosity with a broad range of human phenotypes.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.

The genetic landscape of Scotland and the Isles.

Britain and Ireland are known to show population genetic structure; however, large swathes of Scotland, in particular, have yet to be described. Delineating the structure and ancestry of these populations will allow variant discovery efforts to focus efficiently on areas not represented in existing cohorts. Thus, we assembled genotype data for 2,554 individuals from across the entire archipelago with geographically restricted ancestry, and performed population structure analyses and comparisons to ancient DNA. Extensive geographic structuring is revealed, from broad scales such as a NE to SW divide in mainland Scotland, through to the finest scale observed to date: across 3 km in the Northern Isles. Many genetic boundaries are consistent with Dark Age kingdoms of Gaels, Picts, Britons, and Norse. Populations in the Hebrides, the Highlands, Argyll, Donegal, and the Isle of Man show characteristics of isolation. We document a pole of Norwegian ancestry in the north of the archipelago (reaching 23 to 28% in Shetland) which complements previously described poles of Germanic ancestry in the east, and "Celtic" to the west. This modern genetic structure suggests a northwestern British or Irish source population for the ancient Gaels that contributed to the founding of Iceland. As rarer variants, often with larger effect sizes, become the focus of complex trait genetics, more diverse rural cohorts may be required to optimize discoveries in British and Irish populations and their considerable global diaspora.

Publisher Correction: Parent of origin genetic effects on methylation in humans are common and influence complex trait variation.

In the original version of this Article, the legend in the upper panel of Figure 2 incorrectly read 'paternal imprinting' and should have read 'maternal imprinting'. This has been corrected in both the PDF and HTML versions of the Article.

Parent of origin genetic effects on methylation in humans are common and influence complex trait variation.

Parent-of-origin effects (POE) exist when there is differential expression of alleles inherited from the two parents. A genome-wide scan for POE on DNA methylation at 639,238 CpGs in 5,101 individuals identifies 733 independent methylation CpGs potentially influenced by POE at a false discovery rate ≤ 0.05 of which 331 had not previously been identified. Cis and trans methylation quantitative trait loci (mQTL) regulate methylation variation through POE at 54% (399/733) of the identified POE-influenced CpGs. The combined results provide strong evidence for previously unidentified POE-influenced CpGs at 171 independent loci. Methylation variation at 14 of the POE-influenced CpGs is associated with multiple metabolic traits. A phenome-wide association analysis using the POE mQTL SNPs identifies a previously unidentified imprinted locus associated with waist circumference. These results provide a high resolution population-level map for POE on DNA methylation sites, their local and distant regulators and potential consequences for complex traits.

Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences.

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.

Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances.

We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify and replicate novel findings near ABO, ZC3HC1, and IGF2R. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer - but not other cancers - explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Ageing happens to us all, and as the cabaret singer Maurice Chevalier pointed out, "old age is not that bad when you consider the alternative". Yet, the growing ageing population of most developed countries presents challenges to healthcare systems and government finances. For many older people, long periods of ill health are part of the end of life, and so a better understanding of ageing could offer the opportunity to prolong healthy living into old age. Ageing is complex and takes a long time to study ­ a lifetime in fact. This makes it difficult to discern its causes, among the countless possibilities based on an individual's genes, behaviour or environment. While thousands of regions in an individual's genetic makeup are known to influence their risk of different diseases, those that affect how long they will live have proved harder to disentangle. Timmers et al. sought to pinpoint such regions, and then use this information to predict, based on their DNA, whether someone had a better or worse chance of living longer than average. The DNA of over 500,000 people was read to reveal the specific 'genetic fingerprints' of each participant. Then, after asking each of the participants how long both of their parents had lived, Timmers et al. pinpointed 12 DNA regions that affect lifespan. Five of these regions were new and had not been linked to lifespan before. Across the twelve as a whole several were known to be involved in Alzheimer's disease, smoking-related cancer or heart disease. Looking at the entire genome, Timmers et al. could then predict a lifespan score for each individual, and when they sorted participants into ten groups based on these scores they found that top group lived five years longer than the bottom, on average. Many factors beside genetics influence how long a person will live and our lifespan cannot be read from our DNA alone. Nevertheless, Timmers et al. had hoped to narrow down their search and discover specific genes that directly influence how quickly people age, beyond diseases. If such genes exist, their effects were too small to be detected in this study. The next step will be to expand the study to include more participants, which will hopefully pinpoint further genomic regions and help disentangle the biology of ageing and disease.

International assessment of inter- and intrarater reliability of the International Frontal Sinus Anatomy Classification system.

BACKGROUND: Inconsistencies in the nomenclature of structures of the frontal sinus have impeded the development of a validated "reference standard" classification system that surgeons can reliably agree upon. The International Frontal Sinus Anatomy Classification (IFAC) system was developed as a consensus document, based on expert opinion, attempting to address this issue. The purposes of this study are to: establish the reliability of the IFAC as a tool for classifying cells in the frontal recess among an international group of rhinologists; and improve communication and teaching of frontal endoscopic sinus surgery (ESS). METHODS: Forty-two computed tomography (CT) scans, each with a marked frontal cell, were reviewed by 15 international fellowship-trained rhinologists. Each marked cell was classified into 1 of 7 categories described in the IFAC, on 2 occasions separated by 2 weeks. Inter- and intrarater reliability were evaluated using Light's kappa (κ), the interclass correlation coefficient (ICC), and simple proportion of agreement. RESULTS: Interrater reliability showed pairwise κ values ranging from 0.7248 to 1.0, with a mean of 0.9162 (SD, 0.0537). The ICC was 0.98. Intrarater reliability showed κ values ranging from 0.8613 to 1.0, with a mean of 0.9407 (SD, 0.0376). The within-rater ICC was 0.98. CONCLUSION: Among a diverse sample of rhinologists (raters), there was substantial to almost perfect agreement between raters, and among individual raters at different timepoints. The IFAC is a reliable tool for classification of cells in the frontal sinus. Further outcome studies are still needed to determine the validity of the IFAC.

Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

Nasal airway obstruction: Prevalence and anatomic contributors.

Surgical treatments for nasal airway obstruction (NAO) are commonly offered as part of otolaryngology practice. Anatomic causes include septal deviation, inferior turbinate hypertrophy, and nasal valve collapse (NVC). This study was performed to determine the prevalence of anatomic contributors to NAO. A total of 1,906 patients with sinonasal complaints were surveyed by 50 otolaryngologists in varying U.S. geographic regions. Patients were first evaluated using the Nasal Obstruction Symptom Evaluation (NOSE) instrument to assess the NAO symptoms and their severity. Physicians then examined patients for the presence of the three anatomic contributors. Presence of septal deviation and turbinate hypertrophy was assessed through an internal nasal exam with direct or endoscopic visualization based on the physician's standard methodology for diagnosis. Presence of NVC was determined by the modified Cottle maneuver. Among all patients surveyed, prevalence was 67% for NVC, 76% for septal deviation, and 72% for inferior turbinate hypertrophy. We found that 64% of the patients (n = 1,211) had severe/extreme NOSE scores (≥55), representing the most likely nasal obstruction candidates for intervention. In these patients, the prevalence of NVC, septal deviation, and inferior turbinate hypertrophy was 73, 80, and 77%, respectively. Eighty-two percent of the 236 patients with severe/extreme NOSE scores who reported prior septoplasty and/or inferior turbinate reduction had NVC. Our study revealed a comparable prevalence of all three anatomic contributors across all patients and the subset with severe/extreme NOSE scores, highlighting the importance of evaluating the lateral nasal wall as a component of NAO treatment strategy.

RAD6 promotes chemoresistance in ovarian cancer.

Mortality in ovarian cancer is predominantly due to acquired chemoresistance and tumor recurrence. UBIQUITIN CONJUGATING ENZYME E2 or RAD6 expression increases in cell lines and patient tumors in response to platinum-based chemotherapy and promotes both activation of DNA damage response pathways and expression of stemness genes and a stem cell-like phenotype driving ovarian cancer chemoresistance.

Runs of homozygosity: windows into population history and trait architecture.

Long runs of homozygosity (ROH) arise when identical haplotypes are inherited from each parent and thus a long tract of genotypes is homozygous. Cousin marriage or inbreeding gives rise to such autozygosity; however, genome-wide data reveal that ROH are universally common in human genomes even among outbred individuals. The number and length of ROH reflect individual demographic history, while the homozygosity burden can be used to investigate the genetic architecture of complex disease. We discuss how to identify ROH in genome-wide microarray and sequence data, their distribution in human populations and their application to the understanding of inbreeding depression and disease risk.

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.

Multifocal sinonasal inverted papilloma with middle ear involvement.

Inverted papilloma of the nasal cavity is a benign neoplasm, although it can be locally invasive and has the potential for malignant degeneration. Inverted papilloma of the temporal bone is extremely rare. We describe a case of a 44-year-old woman who was treated for nasal inverted papilloma and was later found to have inverted papilloma of her temporal bone. The patient required several procedures to remove the inverted papilloma from the nasal cavity and temporal bone, and she is currently free of recurrence.

Submandibular neck mass in a newborn.

A deep neck abscess is uncommon in the newborn period. In this case, we noted a clindamycin-sensitive methicillin-resistant Staphylococcus aureus infection characterized as a deep neck abscess in an 8-day-old boy. He was admitted to the pediatric intensive care unit with a progressively enlarging indurated mass below the mandible. Imaging confirmed the mass as a submandibular abscess. The patient received antibiotics in addition to incision and drainage, with resolution of the abscess.