Effect of Loss-of-Function Genetic Variants in PCSK9 on Glycemic Traits, Neurocognitive Impairment, and Hepatobiliary Function

Esophageal atresias/tracheoesophageal fistulas (EA/TEF) are rare congenital anomalies caused by aberrant development of the foregut. Previous studies indicate that rare or de novo genetic variants significantly contribute to EA/TEF risk, and most individuals with EA/TEF do not have pathogenic genetic variants in established risk genes. To identify novel genetic contributions to EA/TEF, we performed whole genome sequencing of 185 trios (probands and parents) with EA/TEF, including 59 isolated and 126 complex cases with additional congenital anomalies and/or neurodevelopmental disorders. There was a significant burden of protein altering de novo coding variants in complex cases (p=3.3e-4), especially in genes that are intolerant of loss of function variants in the population. We performed simulation analysis of pathway enrichment based on background mutation rate and identified a number of pathways related to endocytosis and intracellular trafficking that as a group have a significant burden of protein altering de novo variants. We assessed 18 variants for disease causality using CRISPR-Cas9 mutagenesis in Xenopus and confirmed 13 with tracheoesophageal phenotypes. Our results implicate disruption of endosome-mediated epithelial remodeling as a potential mechanism of foregut developmental defects. This research may have implications for the mechanisms of other rare congenital anomalies.

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High-impact rare genetic variants in severe schizophrenia

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2112560118 ◽

2021 ◽

Vol 118 (51) ◽

pp. e2112560118

Author(s):

Anthony W. Zoghbi ◽

Ryan S. Dhindsa ◽

Terry E. Goldberg ◽

Aydan Mehralizade ◽

Joshua E. Motelow ◽

...

Keyword(s):

Genetic Variants ◽

Odds Ratio ◽

High Impact ◽

Psychiatric Genetics ◽

Loss Of Function ◽

Treatment Resistant ◽

Complex Disorders ◽

Extreme Phenotype ◽

Case Selection ◽

Rare Genetic Variants

Extreme phenotype sequencing has led to the identification of high-impact rare genetic variants for many complex disorders but has not been applied to studies of severe schizophrenia. We sequenced 112 individuals with severe, extremely treatment-resistant schizophrenia, 218 individuals with typical schizophrenia, and 4,929 controls. We compared the burden of rare, damaging missense and loss-of-function variants between severe, extremely treatment-resistant schizophrenia, typical schizophrenia, and controls across mutation intolerant genes. Individuals with severe, extremely treatment-resistant schizophrenia had a high burden of rare loss-of-function (odds ratio, 1.91; 95% CI, 1.39 to 2.63; P = 7.8 × 10−5) and damaging missense variants in intolerant genes (odds ratio, 2.90; 95% CI, 2.02 to 4.15; P = 3.2 × 10−9). A total of 48.2% of individuals with severe, extremely treatment-resistant schizophrenia carried at least one rare, damaging missense or loss-of-function variant in intolerant genes compared to 29.8% of typical schizophrenia individuals (odds ratio, 2.18; 95% CI, 1.33 to 3.60; P = 1.6 × 10−3) and 25.4% of controls (odds ratio, 2.74; 95% CI, 1.85 to 4.06; P = 2.9 × 10−7). Restricting to genes previously associated with schizophrenia risk strengthened the enrichment with 8.9% of individuals with severe, extremely treatment-resistant schizophrenia carrying a damaging missense or loss-of-function variant compared to 2.3% of typical schizophrenia (odds ratio, 5.48; 95% CI, 1.52 to 19.74; P = 0.02) and 1.6% of controls (odds ratio, 5.82; 95% CI, 3.00 to 11.28; P = 2.6 × 10−8). These results demonstrate the power of extreme phenotype case selection in psychiatric genetics and an approach to augment schizophrenia gene discovery efforts.

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PTEN Protein losses and loss-of-function genetic variants in gastric cancers: the relationship with microsatellite instability, EBV, and PD-L1 expression

Pathology ◽

10.1016/j.pathol.2020.01.409 ◽

2020 ◽

Vol 52 ◽

pp. S120

Author(s):

Binnari Kim ◽

So Young Kang ◽

Deokgeun Kim ◽

Eun Ji Kim ◽

You Jeong Heo ◽

...

Keyword(s):

Microsatellite Instability ◽

Genetic Variants ◽

Loss Of Function ◽

Pten Protein ◽

Gastric Cancers ◽

The Relationship

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TCT-171: Cytochrome P450 2C19 Loss-Of-Function Genetic Variants but not Paraoxonase-1 Activity Modulate P2Y12 Blockade in Response to Clopidogrel Therapy

Journal of the American College of Cardiology ◽

10.1016/j.jacc.2011.10.177 ◽

2011 ◽

Vol 58 (20) ◽

pp. B45 ◽

Cited By ~ 1

Keyword(s):

Cytochrome P450 ◽

Genetic Variants ◽

Paraoxonase 1 ◽

Loss Of Function ◽

Cytochrome P450 2C19 ◽

Clopidogrel Therapy

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Exome sequencing identifies novel AD-associated genes.

10.1101/2020.07.22.20159251 ◽

2020 ◽

Cited By ~ 1

Author(s):

Henne Holstege ◽

Marc Hulsman ◽

Camille Charbonnier ◽

Benjamin Grenier-Boley ◽

Olivier Quenez ◽

...

Keyword(s):

Exome Sequencing ◽

Genetic Variants ◽

Rare Variants ◽

Mendelian Inheritance ◽

Loss Of Function ◽

App Processing ◽

Complex Disorders ◽

Pathogenic Variants ◽

Increased Risk ◽

The Impact

Background: With the development of next-generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimers Disease (AD), reaching odds ratios comparable with the APOE-ε4 allele, the main common AD genetic risk factor. Here, we set out to identify additional AD-associated genes by an exome-wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls. Method: We integrated the data from 25,982 samples from the European ADES consortium and the American ADSP consortium. We developed new techniques to homogenise and analyse these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of dementia were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analysed using a burden analysis, including both non-synonymous and loss-of-function rare variants, the impact of which was prioritised using REVEL. Result: We confirmed that carrying rare protein-damaging genetic variants in TREM2, SORL1 or ABCA7 is associated with increased AD-risk. Moreover, we found that carrying rare damaging variants in the microglial ATP8B4 gene was significantly associated with AD, and we found suggestive evidence that rare variants in ADAM10, ABCA1, ORC6, B3GNT4 and SRC genes associated with increased AD risk. High-impact variants in these genes were mostly extremely rare and enriched in AD patients with earlier ages at onset. Additionally, we identified two suggestive protective associations in CBX3 and PRSS3. We are currently replicating these associations in independent datasets. Conclusion: With our newly developed homogenisation methods, we identified novel genetic determinants of AD which provide further evidence for a pivotal role of APP processing, lipid metabolism, and microglia and neuro-inflammatory processes in AD pathophysiology.

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ANGPTL3 Gene Variants in Subjects With Familial Combined Hyperlipidemia

10.21203/rs.3.rs-134198/v1 ◽

2021 ◽

Author(s):

Ana Bea ◽

Esther Franco-Marin ◽

Victoria Marco-Benedí ◽

Estíbaliz Jarauta ◽

Irene Gracia-Rubio ◽

...

Keyword(s):

Lipid Metabolism ◽

Genetic Variants ◽

Monogenic Disease ◽

Potential Contribution ◽

Gene Variants ◽

Loss Of Function ◽

Familial Combined Hyperlipidemia ◽

Gain Of Function ◽

Large Group

Abstract Angiopoietin-like 3 (ANGPTL3) plays an important role in lipid metabolism in humans. Loss-of-function variants in ANGPTL3 cause a monogenic disease named familial combined hypolipidemia. However, the potential contribution of ANGPTL3 gene in subjects with familial combined hyperlipidemia (FCHL) has not been studied. To study the gain-of-function (GOF) genetic variants in the ANGPTL3 gene in FCHL subjects and to establish the potential contribution of ANGPTL3 in the aetiology of FCHL. ANGPTL3 gene was sequenced in 162 unrelated subjects with severe FCHL and 165 normolipemic controls. Pathogenicity of genetic variants was predicted with PredictSNP2 and FruitFly. Frequency of identified variants in FCHL was compared with that of normolipemic controls and that described in the1000 Genomes Project. No GOF mutations in ANGPTL3 was present in subjects with FCHL. Four variants were identified in FCHL subjects, showing a frequency different from that observed in normolipemic controls: c.607-109T>C, c.607-47_607-46delGT, c.835+41C>A and c.*52_*60del. This last variant, c.*52_*60del, is a microRNA associated sequence in the 3’UTR of ANGPTL3, and it was present 2.7 times more frequently in normolipemic controls than in FCHL subjects. Our research shows that no GOF mutations in ANGPTL3 were found in a large group of unrelated subjects with FCHL.

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Genome-enabled inference of functional genetic variants in the face, brain and behavior

10.1101/2020.10.12.336453 ◽

2020 ◽

Author(s):

Chinar Patil ◽

Jonathan B. Sylvester ◽

Kawther Abdilleh ◽

Michael W. Norsworthy ◽

Karen Pottin ◽

...

Keyword(s):

Genetic Variants ◽

Reverse Genetics ◽

Natural Populations ◽

Bmp Signaling ◽

Loss Of Function ◽

Genetic Changes ◽

Form And Function ◽

Functional Variants ◽

Brain And Behavior ◽

And Function

AbstractLake Malawi cichlid fishes exhibit extensive divergence in form and function among closely related species separated by a relatively small number of genetic changes. During the past million years, hundreds of species have diversified along an ecological axis in rock vs. sand habitats. We compared the genomes of rock- and sand-dwelling species and asked which genetic variants in which genes differed among the groups. We found that 96% of differentiated variants reside in non-coding sequence but these non-coding diverged variants are evolutionarily conserved. The majority of divergent coding variants are missense and/or loss of function. Regions near differentiated variants are enriched for craniofacial, neural and behavioral functional categories. To follow up experimentally, we used rock- vs. sand-species and their hybrids to (i) clarify the push-pull roles of BMP signaling and irx1b in the specification of forebrain territories during gastrulation and (ii) reveal striking context-dependent brain gene expression during adult social behavior. Our results suggest compelling ties between early brain development and adult behavior and highlight the promise of evolutionary reverse genetics – the identification of functional variants from genome sequencing in natural populations.

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Genetic variants of human organic anion transporter 4 demonstrate altered transport of endogenous substrates

AJP Renal Physiology ◽

10.1152/ajprenal.00312.2010 ◽

2010 ◽

Vol 299 (4) ◽

pp. F767-F775 ◽

Cited By ~ 19

Author(s):

James E. Shima ◽

Takafumi Komori ◽

Travis R. Taylor ◽

Doug Stryke ◽

Michiko Kawamoto ◽

...

Keyword(s):

Genetic Variants ◽

Drug Disposition ◽

Organic Anion ◽

Functional Characterization ◽

Organic Anion Transporter ◽

Loss Of Function ◽

Anion Transporter ◽

Endogenous Substrates ◽

Slc Transporter

Apical reabsorption from the urine has been shown to be important for such processes as the maintenance of critical metabolites in the blood and the excretion of nephrotoxic compounds. The solute carrier (SLC) transporter OAT4 ( SLC22A11) is expressed on the apical membrane of renal proximal tubule cells and is known to mediate the transport of a variety of xenobiotic and endogenous organic anions. Functional characterization of genetic variants of apical transporters thought to mediate reabsorption, such as OAT4, may provide insight into the genetic factors influencing the complex pathways involved in drug elimination and metabolite reclamation occurring in the kidney. Naturally occurring genetic variants of OAT4 were identified in public databases and by resequencing DNA samples from 272 individuals comprising 4 distinct ethnic groups. Nine total nonsynonymous variants were identified and functionally assessed using uptake of three radiolabeled substrates. A nonsense variant, R48Stop, and three other variants (R121C, V155G, and V155M) were found at frequencies of at least 2% in an ethnic group specific fashion. The L29P, R48Stop, and H469R variants displayed a complete loss of function, and kinetic analysis identified a reduced Vmax in the common nonsynonymous variants. Plasma membrane levels of OAT4 protein were absent or reduced in the nonfunctional variants, providing a mechanistic reason for the observed loss of function. Characterization of the genetic variants of reabsorptive transporters such as OAT4 is an important step in understanding variability in tubular reabsorption with important implications in innate homeostatic processes and drug disposition.

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NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

Mucosal Immunology ◽

10.1038/mi.2017.74 ◽

2017 ◽

Vol 11 (2) ◽

pp. 562-574 ◽

Cited By ~ 33

Author(s):

T Schwerd ◽

◽

R V Bryant ◽

S Pandey ◽

M Capitani ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Genetic Variants ◽

Loss Of Function ◽

Inflammatory Bowel

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Whole-genome sequencing reveals KRTAP1-1 as a novel genetic variant associated with antidepressant treatment outcomes

Scientific Reports ◽

10.1038/s41598-021-83887-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jong-Ho Park ◽

Shinn-Won Lim ◽

Woojae Myung ◽

Inho Park ◽

Hyeok-Jae Jang ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Treatment Outcomes ◽

Genetic Markers ◽

Genome Sequencing ◽

Genetic Variants ◽

Selective Serotonin Reuptake Inhibitors ◽

Remission Rate ◽

Antidepressant Treatment ◽

Whole Genome ◽

Loss Of Function

AbstractAchieving remission following initial antidepressant therapy in patients with major depressive disorder (MDD) is an important clinical result. Making predictions based on genetic markers holds promise for improving the remission rate. However, genetic variants found in previous genetic studies do not provide robust evidence to aid pharmacogenetic decision-making in clinical settings. Thus, the objective of this study was to perform whole-genome sequencing (WGS) using genomic DNA to identify genetic variants associated with the treatment outcomes of selective serotonin reuptake inhibitors (SSRIs). We performed WGS on 100 patients with MDD who were treated with escitalopram (discovery set: 36 remitted and 64 non-remitted). The findings were applied to an additional 553 patients with MDD who were treated with SSRIs (replication set: 185 remitted and 368 non-remitted). A novel loss-of-function variant (rs3213755) in keratin-associated protein 1–1 (KRTAP1-1) was identified in this study. This rs3213755 variant was significantly associated with remission following antidepressant treatment (p = 0.0184, OR 3.09, 95% confidence interval [CI] 1.22–7.80 in the discovery set; p = 0.00269, OR 1.75, 95% CI 1.22–2.53 in the replication set). Moreover, the expression level of KRTAP1-1 in surgically resected human temporal lobe samples was significantly associated with the rs3213755 genotype. WGS studies on a larger sample size in various ethnic groups are needed to investigate genetic markers useful in the pharmacogenetic prediction of remission following antidepressant treatment.

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