Variants in USP48 encoding ubiquitin hydrolase are associated with autosomal dominant non-syndromic hereditary hearing loss.

Non-Syndromic Hereditary Hearing Loss (NSHHL) is a genetically heterogeneous sensory disorder with about 120 genes already associated. Through exome sequencing (ES) and data aggregation, we identified a family with six affected individuals and one unrelated NSHHL patient with predicted-to-be deleterious missense variants in USP48. We also uncovered an eighth patient presenting unilateral cochlear nerve aplasia and a de novo splice variant in the same gene. USP48 encodes a ubiquitin carboxyl-terminal hydrolase under evolutionary constraint. Pathogenicity of the variants is supported by in vitro assays that showed that the mutated proteins are unable to hydrolyze tetra-ubiquitin. Correspondingly, three-dimensional representation of the protein containing the familial missense variant is situated in a loop that might influence the binding to ubiquitin. Consistent with a contribution of USP48 to auditory function, immunohistology showed that the encoded protein is expressed in the developing human inner ear, specifically in the spiral ganglion neurons, outer sulcus, interdental cells of the spiral limbus, stria vascularis, Reissner's membrane and in the transient Kolliker's organ that is essential for auditory development. Engineered zebrafish knocked-down for usp48, the USP48 ortholog, presented with a delayed development of primary motor neurons, less developed statoacoustic neurons innervating the ears, decreased swimming velocity and circling swimming behavior indicative of vestibular dysfunction and hearing impairment. Corroboratingly, acoustic startle response assays revealed a significant decrease of auditory response of zebrafish lacking usp48 at 600 and 800 Hz wavelengths. In conclusion, we describe a novel autosomal dominant NSHHL gene through a multipronged approach combining ES, animal modeling, immunohistology and molecular assays.

Insights into gene tissue specificity and protein-protein interactions in the context of purifying selection in humans.

BACKGROUND: How much are natural selection and gene characteristics, such as the number of protein-protein interactions (PPIs), tissue specificity (𝞽), and expression level, connected? METHODS: In order to investigate these relationships, we combined different metrics linked to genetic constraints and analyzed their distribution concerning PPIs, 𝞽 and expression levels. RESULTS: We discovered a positive correlation between genetic constraints, PPIs, and expression levels in all tissues. On the other hand, we obtained a negative correlation between genetic constraints and 𝞽. Furthermore, the fraction of variance in PPI and 𝞽 explained by the constraints metrics is around 6% and 10%, respectively. CONCLUSIONS: We observed that the variance of expression of tissue-specific genes seems not related to their level of selection constraints, which is the opposite of what is found on non-tissue-specific genes. Overall these observations would help to elucidate the relationship between natural selection and gene features.

Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin.

BACKGROUND: Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown. METHODS: We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing. RESULTS: Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. CONCLUSIONS: Common variants in KRT40, WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.

Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies.

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

A population-based approach for gene prioritization in understanding complex traits.

Gene prioritization is the process of determining which variants and genes identified in genetic analyses are likely to cause a disease or a variation in a phenotype. For many genes, neither in vitro nor in vivo testing is available, thus assessing their pathogenic role could be challenging, leading to false-positive or false-negative results. In this paper, we propose an innovative score of gene prioritization based on the population of interest. We introduce the concept of singleton-cohort variants (SC variant), a variant that has allele count equal to one in the cohort under study. The difference between the normalized count of SC variants in the coding region and the normalized count of SC variants in the non-coding region should give a hint regarding the level of constraints for that gene in a specific population. This scoring system is negative when there are constraints that allow the presence of SC variants only in the non-coding region; on the contrary, it is positive when there are no constraints. A complimentary score is the sum of SC variants normalized count in both coding and non-coding regions, which could be used as a proxy of positive or strong purifying selection in a specific population. Our methodology showed a high level of constraining for genes such as USP34 in all subpopulations tested (1000 G dataset). In contrast, some genes showed a high negative score only in specific populations, e.g., MYT1L in Europeans, UBR5 in East Asians, and FBXO11 in Africans.

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits.

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.

COL6A5 variants in familial neuropathic chronic itch.

Itch is thought to represent the peculiar response to stimuli conveyed by somatosensory pathways shared with pain through the activation of specific neurons and receptors. It can occur in association with dermatological, systemic and neurological diseases, or be the side effect of certain drugs. However, some patients suffer from chronic idiopathic itch that is frequently ascribed to psychological distress and for which no biomarker is available to date. We investigated three multigenerational families, one of which diagnosed with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT), characterized by idiopathic chronic itch with predominantly proximal distribution. Skin biopsy was performed in all eight affected members and revealed in six of them reduced intraepidermal nerve fibre density consistent with small fibre neuropathy. Whole exome sequencing identified two COL6A5 rare variants co-segregating with chronic itch in eight affected members and absent in non-affected members, and in one unrelated sporadic patient with type 1 painless diabetic neuropathy and chronic itch. Two families and the diabetic patient carried the nonsense c.6814G>T (p.Glu2272*) variant and another family carried the missense c.6486G>C (p.Arg2162Ser) variant. Both variants were predicted as likely pathogenic by in silico analyses. The two variants were rare (minor allele frequency < 0.1%) in 6271 healthy controls and absent in 77 small fibre neuropathy and 167 JHS/EDS-HT patients without itch. Null-allele test on cDNA from patients' fibroblasts of both families carrying the nonsense variant demonstrated functional haploinsufficiency due to activation of nonsense mediated RNA decay. Immunofluorescence microscopy and western blotting revealed marked disorganization and reduced COL6A5 synthesis, respectively. Indirect immunofluorescence showed reduced COL6A5 expression in the skin of patients carrying the nonsense variant. Treatment with gabapentinoids provided satisfactory itch relief in the patients carrying the mutations. Our findings first revealed an association between COL6A5 gene and familiar chronic itch, suggesting a new contributor to the pathogenesis of neuropathic itch and identifying a new candidate therapeutic target.

A general approach for haplotype phasing across the full spectrum of relatedness.

Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally 'unrelated' individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.

Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

Pharmacogenetics driving personalized medicine: analysis of genetic polymorphisms related to breast cancer medications in Italian isolated populations.

BACKGROUND: Breast cancer is the most common cancer in women characterized by a high variable clinical outcome among individuals treated with equivalent regimens and novel targeted therapies. In this study, we performed a population based approach intersecting high-throughput genotype data from Friuli Venezia Giulia (FVG) isolated populations with publically available pharmacogenomics information to estimate the frequency of genotypes correlated with responsiveness to breast cancer treatment thus improving the clinical management of this disease in an efficient and cost effective way. METHODS: A list of 80 variants reported to be related to the efficacy or toxicity of breast cancer drugs was obtained from PharmGKB database. Fourty-one were present in FVG, 1000G European (EUR) and ExAC (Non Finnish European) databases. Their frequency was extracted using PLINK software and the differences tested by Fisher's exact test. RESULTS: Statistical analyses revealed that 13 out of the 41 (32 %) variants were significantly different in frequency in our sample as compared to the EUR/ExAC cohorts. For nine variants the available level of evidence (LOE) included polymorphisms related to cyclophosphamide, tamoxifen, doxorubicin, fluorpyrimidine and paclitaxel. In particular, for trastuzumab two variants were detected: (1) rs1801274-G within FCGR2A and associated with decreased efficacy (LOE 2B); (2) rs1136201-G located within ERBB2 and associated with increased toxicity (LOE 3). Both these two variants were underrepresented in the FVG population compared to EUR/ExAC population thus suggesting a high therapeutic index of this drug in our population. Moreover, as regards fluoropyrimidines, the frequency of two polymorphisms within the DPYD gene associated with drug toxicity (e.g., rs2297595-C allele and rs3918290-T allele, LOE 2A and 1, respectively) was extremely low in FVG population thus suggesting that a larger number of FVG patients could benefit from full dosage of fluoropyrimidine therapy. CONCLUSIONS: All these findings increase the overall knowledge on the prevalence of specific variants related with breast cancer treatment responsiveness in FVG population and highlight the importance of assessing gene polymorphisms related with cancer medications in isolated communities.

Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis.

Uromodulin is expressed exclusively in the thick ascending limb and is the most abundant protein excreted in normal urine. Variants in UMOD, which encodes uromodulin, are associated with renal function, and urinary uromodulin levels may be a biomarker for kidney disease. However, the genetic factors regulating uromodulin excretion are unknown. We conducted a meta-analysis of urinary uromodulin levels to identify associated common genetic variants in the general population. We included 10,884 individuals of European descent from three genetic isolates and three urban cohorts. Each study measured uromodulin indexed to creatinine and conducted linear regression analysis of approximately 2.5 million single nucleotide polymorphisms using an additive model. We also tested whether variants in genes expressed in the thick ascending limb associate with uromodulin levels. rs12917707, located near UMOD and previously associated with renal function and CKD, had the strongest association with urinary uromodulin levels (P<0.001). In all cohorts, carriers of a G allele of this variant had higher uromodulin levels than noncarriers did (geometric means 10.24, 14.05, and 17.67 µg/g creatinine for zero, one, or two copies of the G allele). rs12446492 in the adjacent gene PDILT (protein disulfide isomerase-like, testis expressed) also reached genome-wide significance (P<0.001). Regarding genes expressed in the thick ascending limb, variants in KCNJ1, SORL1, and CAB39 associated with urinary uromodulin levels. These data indicate that common variants in the UMOD promoter region may influence urinary uromodulin levels. They also provide insights into uromodulin biology and the association of UMOD variants with renal function.

X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus.

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.

Genetic insights into resting heart rate and its role in cardiovascular disease.

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Association of HFE and TMPRSS6 genetic variants with iron and erythrocyte parameters is only in part dependent on serum hepcidin concentrations.

BACKGROUND: Hepcidin is the main regulator of iron homeostasis: inappropriate production of hepcidin results in iron overload or iron deficiency and anaemia. AIMS: To study variation of serum hepcidin concentration in a normal population. RESULTS: Hepcidin showed age and sex dependent variations that correlated with ferritin but not with serum iron and transferrin saturation. The size of the study population was underpowered to find genome wide significant associations with hepcidin concentrations but it allowed to show that association with serum iron, transferrin saturation and erythrocyte traits of common DNA variants in HFE (rs1800562) and TMPRSS6 (rs855791) genes is not exclusively dependent on hepcidin values. When multiple interactions between environmental factors, the iron parameters and hepcidin were taken into account, the HFE variant, and to lesser extent the TMPRSS6 variant, were associated with ferritin and with hepcidin normalised to ferritin (the hepcidin/ferritin ratio). CONCLUSIONS: The results suggest a mutual control of serum hepcidin and ferritin concentrations, a mechanism relevant to the pathophysiology of HFE haemochromatosis, and demonstrate that the HFE rs1800562 C282Y variant exerts a direct pleiotropic effect on the iron parameters, in part independent of hepcidin.

Ancestry-related distribution of Runs of homozygosity and functional variants in Qatari population.

BACKGROUND: Describing how genetic history shapes the pattern of medically relevant variants could improve the understanding of how specific loci interact with each other and affect diseases and traits prevalence. The Qatari population is characterized by a complex history of admixture and substructure, and the study of its population genomic features would provide valuable insights into the genetic landscape of functional variants. Here, we analyzed the genomic variation of 186 newly-genotyped healthy individuals from the Qatari peninsula. RESULTS: We discovered an intricate genetic structure using ancestry related analyses. In particular, the presence of three different clusters, Cluster 1, Cluster 2 and Cluster 3 (with Near Eastern, South Asian and African ancestry, respectively), was detected with an additional fourth one (Cluster 4) with East Asian ancestry. These subpopulations show differences in the distribution of runs of homozygosity (ROH) and admixture events in the past, ranging from 40 to 5 generations ago. This complex genetic history led to a peculiar pattern of functional markers under positive selection, differentiated in shared signals and private signals. Interestingly we found several signatures of shared selection on SNPs in the FADS2 gene, hinting at a possible common evolutionary link to dietary intake. Among the private signals, we found enrichment for markers associated with HDL and LDL for Cluster 1(Near Eastern ancestry) and Cluster 3 (South Asian ancestry) and height and blood traits for Cluster 2 (African ancestry). The differences in genetic history among these populations also resulted in the different frequency distribution of putative loss of function variants. For example, homozygous carriers for rs2884737, a variant linked to an anticoagulant drug (warfarin) response, are mainly represented by individuals with predominant Bedouin ancestry (risk allele frequency G at 0.48). CONCLUSIONS: We provided a detailed catalogue of the different ancestral pattern in the Qatari population highlighting differences and similarities in the distribution of selected variants and putative loss of functions. Finally, these results would provide useful guidance for assessing genetic risk factors linked to consanguinity and genetic ancestry.

Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.

Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways.

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

The Role of Knockout Olfactory Receptor Genes in Odor Discrimination.

To date, little is known about the role of olfactory receptor (OR) genes on smell performance. Thanks to the availability of whole-genome sequencing data of 802 samples, we identified 41 knockout (KO) OR genes (i.e., carriers of Loss of Function variants) and evaluated their effect on odor discrimination in 218 Italian individuals through recursive partitioning analysis. Furthermore, we checked the expression of these genes in human and mouse tissues using publicly available data and the presence of organ-related diseases in human KO (HKO) individuals for OR expressed in non-olfactory tissues (Fisher test). The recursive partitioning analysis showed that age and the high number (burden) of OR-KO genes impact the worsening of odor discrimination (p-value < 0.05). Human expression data showed that 33/41 OR genes are expressed in the olfactory system (OS) and 27 in other tissues. Sixty putative mouse homologs of the 41 humans ORs have been identified, 58 of which are expressed in the OS and 37 in other tissues. No association between OR-KO individuals and pathologies has been detected. In conclusion, our work highlights the role of the burden of OR-KO genes in worse odor discrimination.