@article {894, title = {Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.}, journal = {Genome Med}, volume = {13}, year = {2021}, month = {2021 04 21}, pages = {66}, abstract = {

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.

METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants.

RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections.

CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.

}, keywords = {Adult, Aged, Aged, 80 and over, Angiotensin-Converting Enzyme 2, Asthma, Bronchi, Cardiovascular Diseases, COVID-19, Gene Expression, Genetic Variation, Humans, Middle Aged, Obesity, Pulmonary Disease, Chronic Obstructive, Quantitative Trait Loci, Respiratory Mucosa, Risk Factors, SARS-CoV-2, Smoking}, issn = {1756-994X}, doi = {10.1186/s13073-021-00866-2}, author = {Kasela, Silva and Ortega, Victor E and Martorella, Molly and Garudadri, Suresh and Nguyen, Jenna and Ampleford, Elizabeth and Pasanen, Anu and Nerella, Srilaxmi and Buschur, Kristina L and Barjaktarevic, Igor Z and Barr, R Graham and Bleecker, Eugene R and Bowler, Russell P and Comellas, Alejandro P and Cooper, Christopher B and Couper, David J and Criner, Gerard J and Curtis, Jeffrey L and Han, MeiLan K and Hansel, Nadia N and Hoffman, Eric A and Kaner, Robert J and Krishnan, Jerry A and Martinez, Fernando J and McDonald, Merry-Lynn N and Meyers, Deborah A and Paine, Robert and Peters, Stephen P and Castro, Mario and Denlinger, Loren C and Erzurum, Serpil C and Fahy, John V and Israel, Elliot and Jarjour, Nizar N and Levy, Bruce D and Li, Xingnan and Moore, Wendy C and Wenzel, Sally E and Zein, Joe and Langelier, Charles and Woodruff, Prescott G and Lappalainen, Tuuli and Christenson, Stephanie A} } @article {950, title = {8q24 genetic variation and comprehensive haplotypes altering familial risk of prostate cancer.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 03 23}, pages = {1523}, abstract = {

The 8q24 genomic locus is tied to the origin of numerous cancers. We investigate its contribution to hereditary prostate cancer (HPC) in independent study populations of the Nashville Familial Prostate Cancer Study and International Consortium for Prostate Cancer Genetics (combined: 2,836 HPC cases, 2,206 controls of European ancestry). Here we report 433 variants concordantly associated with HPC in both study populations, accounting for 9\% of heritability and modifying age of diagnosis as well as aggressiveness; 183 reach genome-wide significance. The variants comprehensively distinguish independent risk-altering haplotypes overlapping the 648 kb locus (three protective, and four risk (peak odds ratios: 1.5, 4, 5, and 22)). Sequence of the near-Mendelian haplotype reveals eleven causal mutation candidates. We introduce a linkage disequilibrium-based algorithm discerning eight independent sentinel variants, carrying considerable risk prediction ability (AUC = 0.625) for a single locus. These findings elucidate 8q24 locus structure and correlates for clinical prediction of prostate cancer risk.

}, keywords = {Aged, Case-Control Studies, Chromosomes, Human, Pair 8, European Continental Ancestry Group, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Heterozygote, Humans, Linkage Disequilibrium, Male, Middle Aged, Mutation, Prostatic Neoplasms, Protective Factors, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-020-15122-1}, author = {Dupont, William D and Breyer, Joan P and Plummer, W Dale and Chang, Sam S and Cookson, Michael S and Smith, Joseph A and Blue, Elizabeth E and Bamshad, Michael J and Smith, Jeffrey R} } @article {776, title = {Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer.}, journal = {Cancer}, volume = {126}, year = {2020}, month = {2020 08 15}, pages = {3657-3666}, abstract = {

BACKGROUND: Hereditary leiomyomatosis and renal cancer (HLRCC) is a cancer syndrome associated with a germline mutation in fumarate hydratase (FH). The syndrome is associated with cutaneous and uterine leiomyomas, and some patients develop a lethal form of kidney cancer. This study provides estimates for the FH carrier frequency and kidney cancer penetrance.

METHODS: Data sets containing sequencing data for the FH gene were used: the 1000 Genomes Project (1000GP) and the Exome Aggregation Consortium (ExAC). Alterations in the FH gene were characterized on the basis of different variant risk tiers: 1) ClinVar annotated variants, 2) loss-of-function alterations, and 3) highly impactful missense alterations. The cumulative incidence of FH alterations overall and by different world populations was evaluated in 1000GP and ExAC. A lifetime penetrance of HLRCC kidney cancer risk was generated with 3 estimates of the annual incidence.

RESULTS: The overall allele frequencies of tier 1 to 3 FH alterations in the ExAC and 1000GP data sets were 2.54 {\texttimes} 10 (1 in 393) and 1.20 {\texttimes} 10 (1 in 835), respectively. There were differences in the allele frequencies of FH alterations between world populations. Based on various estimates of the percentage of kidney cancers with FH alterations, the lifetime kidney cancer penetrance for carrier estimate 3 in ExAC was 1.7\% to 5.8\%.

CONCLUSIONS: FH alterations are common and are carried by approximately 1 in 1000 individuals according to the more conservative estimates. The lifetime kidney cancer penetrance appears lower than previously estimated. Although databases are not population cohorts, they provide a useful quantitative estimate of rare variants with low penetrance.

}, keywords = {Adult, Exome, Female, Fumarate Hydratase, Gene Frequency, Genetic Predisposition to Disease, Germ-Line Mutation, Heterozygote, Humans, Kidney, Kidney Neoplasms, Leiomyomatosis, Male, Middle Aged, Neoplastic Syndromes, Hereditary, Risk Factors, Skin Neoplasms, Uterine Neoplasms}, issn = {1097-0142}, doi = {10.1002/cncr.32914}, author = {Shuch, Brian and Li, Shantao and Risch, Harvey and Bindra, Ranjit S and McGillivray, Patrick D and Gerstein, Mark} } @article {822, title = {Gene-based analyses of the maternal genome implicate maternal effect genes as risk factors for conotruncal heart defects.}, journal = {PLoS One}, volume = {15}, year = {2020}, month = {2020}, pages = {e0234357}, abstract = {

Congenital heart defects (CHDs) affect approximately 1\% of newborns. Epidemiological studies have identified several genetically-mediated maternal phenotypes (e.g., pregestational diabetes, chronic hypertension) that are associated with the risk of CHDs in offspring. However, the role of the maternal genome in determining CHD risk has not been defined. We present findings from gene-level, genome-wide studies that link CHDs to maternal effect genes as well as to maternal genes related to hypertension and proteostasis. Maternal effect genes, which provide the mRNAs and proteins in the oocyte that guide early embryonic development before zygotic gene activation, have not previously been implicated in CHD risk. Our findings support a role for and suggest new pathways by which the maternal genome may contribute to the development of CHDs in offspring.

}, keywords = {Adult, Case-Control Studies, Child, Preschool, Family, Female, Genetic Testing, Heart Defects, Congenital, Humans, Hypertension, Infant, Infant, Newborn, Male, Maternal Exposure, Maternal Inheritance, Middle Aged, Oocytes, Pregnancy, Prenatal Exposure Delayed Effects, Proteostasis, Risk Factors}, issn = {1932-6203}, doi = {10.1371/journal.pone.0234357}, author = {Sewda, Anshuman and Agopian, A J and Goldmuntz, Elizabeth and Hakonarson, Hakon and Morrow, Bernice E and Musfee, Fadi and Taylor, Deanne and Mitchell, Laura E} } @article {794, title = {Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.}, journal = {Nat Genet}, volume = {52}, year = {2020}, month = {2020 10}, pages = {1046-1056}, abstract = {

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14\% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

}, keywords = {Animals, beta Catenin, Cerebral Palsy, Cyclin D, Cytoskeleton, Drosophila, Exome, Extracellular Matrix, F-Box Proteins, Female, Focal Adhesions, Genetic Predisposition to Disease, Genome, Human, Humans, Male, Mutation, Neurites, rhoB GTP-Binding Protein, Risk Factors, Sequence Analysis, DNA, Signal Transduction, Tubulin, Tumor Suppressor Proteins, Whole Exome Sequencing}, issn = {1546-1718}, doi = {10.1038/s41588-020-0695-1}, author = {Jin, Sheng Chih and Lewis, Sara A and Bakhtiari, Somayeh and Zeng, Xue and Sierant, Michael C and Shetty, Sheetal and Nordlie, Sandra M and Elie, Aureliane and Corbett, Mark A and Norton, Bethany Y and van Eyk, Clare L and Haider, Shozeb and Guida, Brandon S and Magee, Helen and Liu, James and Pastore, Stephen and Vincent, John B and Brunstrom-Hernandez, Janice and Papavasileiou, Antigone and Fahey, Michael C and Berry, Jesia G and Harper, Kelly and Zhou, Chongchen and Zhang, Junhui and Li, Boyang and Zhao, Hongyu and Heim, Jennifer and Webber, Dani L and Frank, MAHlia S B and Xia, Lei and Xu, Yiran and Zhu, Dengna and Zhang, Bohao and Sheth, Amar H and Knight, James R and Castaldi, Christopher and Tikhonova, Irina R and L{\'o}pez-Gir{\'a}ldez, Francesc and Keren, Boris and Whalen, Sandra and Buratti, Julien and Doummar, Diane and Cho, Megan and Retterer, Kyle and Millan, Francisca and Wang, Yangong and Waugh, Jeff L and Rodan, Lance and Cohen, Julie S and Fatemi, Ali and Lin, Angela E and Phillips, John P and Feyma, Timothy and MacLennan, Suzanna C and Vaughan, Spencer and Crompton, Kylie E and Reid, Susan M and Reddihough, Dinah S and Shang, Qing and Gao, Chao and Novak, Iona and Badawi, Nadia and Wilson, Yana A and McIntyre, Sarah J and Mane, Shrikant M and Wang, Xiaoyang and Amor, David J and Zarnescu, Daniela C and Lu, Qiongshi and Xing, Qinghe and Zhu, Changlian and Bilguvar, Kaya and Padilla-Lopez, Sergio and Lifton, Richard P and Gecz, Jozef and MacLennan, Alastair H and Kruer, Michael C} } @article {849, title = {The Parkinson{\textquoteright}s Disease Genome-Wide Association Study Locus Browser.}, journal = {Mov Disord}, volume = {35}, year = {2020}, month = {2020 11}, pages = {2056-2067}, abstract = {

BACKGROUND: Parkinson{\textquoteright}s disease (PD) is a neurodegenerative disease with an often complex component identifiable by genome-wide association studies. The most recent large-scale PD genome-wide association studies have identified more than 90 independent risk variants for PD risk and progression across more than 80 genomic regions. One major challenge in current genomics is the identification of the causal gene(s) and variant(s) at each genome-wide association study locus. The objective of the current study was to create a tool that would display data for relevant PD risk loci and provide guidance with the prioritization of causal genes and potential mechanisms at each locus.

METHODS: We included all significant genome-wide signals from multiple recent PD genome-wide association studies including themost recent PD risk genome-wide association study, age-at-onset genome-wide association study, progression genome-wide association study, and Asian population PD risk genome-wide association study. We gathered data for all genes 1 Mb up and downstream of each variant to allow users to assess which gene(s) are most associated with the variant of interest based on a set of self-ranked criteria. Multiple databases were queried for each gene to collect additional causal data.

RESULTS: We created a PD genome-wide association study browser tool (https://pdgenetics.shinyapps.io/GWASBrowser/) to assist the PD research community with the prioritization of genes for follow-up functional studies to identify potential therapeutic targets.

CONCLUSIONS: Our PD genome-wide association study browser tool provides users with a useful method of identifying potential causal genes at all known PD risk loci from large-scale PD genome-wide association studies. We plan to update this tool with new relevant data as sample sizes increase and new PD risk loci are discovered. {\textcopyright} 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

}, keywords = {Age of Onset, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Neurodegenerative Diseases, Parkinson Disease, Risk Factors}, issn = {1531-8257}, doi = {10.1002/mds.28197}, author = {Grenn, Francis P and Kim, Jonggeol J and Makarious, Mary B and Iwaki, Hirotaka and Illarionova, Anastasia and Brolin, Kajsa and Kluss, Jillian H and Schumacher-Schuh, Artur F and Leonard, Hampton and Faghri, Faraz and Billingsley, Kimberley and Krohn, Lynne and Hall, Ashley and Diez-Fairen, Monica and Peri{\~n}{\'a}n, Maria Teresa and Foo, Jia Nee and Sandor, Cynthia and Webber, Caleb and Fiske, Brian K and Gibbs, J Raphael and Nalls, Mike A and Singleton, Andrew B and Bandres-Ciga, Sara and Reed, Xylena and Blauwendraat, Cornelis} } @article {848, title = {Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 08 20}, pages = {3635}, abstract = {

Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions - familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic background - the probability of disease by age 75 years ranged from 17\% to 78\% for coronary artery disease, 13\% to 76\% for breast cancer, and 11\% to 80\% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant.

}, keywords = {Aged, Breast Neoplasms, Case-Control Studies, Colorectal Neoplasms, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome, Human, Humans, Male, Middle Aged, Multifactorial Inheritance, Odds Ratio, Penetrance, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-020-17374-3}, author = {Fahed, Akl C and Wang, Minxian and Homburger, Julian R and Patel, Aniruddh P and Bick, Alexander G and Neben, Cynthia L and Lai, Carmen and Brockman, Deanna and Philippakis, Anthony and Ellinor, Patrick T and Cassa, Christopher A and Lebo, Matthew and Ng, Kenney and Lander, Eric S and Zhou, Alicia Y and Kathiresan, Sekar and Khera, Amit V} } @article {805, title = {Recurrent Rare Copy Number Variants Increase Risk for Esotropia.}, journal = {Invest Ophthalmol Vis Sci}, volume = {61}, year = {2020}, month = {2020 08 03}, pages = {22}, abstract = {

Purpose: To determine whether rare copy number variants (CNVs) increase risk for comitant esotropia.

Methods: CNVs were identified in 1614 Caucasian individuals with comitant esotropia and 3922 Caucasian controls from Illumina SNP genotyping using two Hidden Markov model (HMM) algorithms, PennCNV and QuantiSNP, which call CNVs based on logR ratio and B allele frequency. Deletions and duplications greater than 10 kb were included. Common CNVs were excluded. Association testing was performed with 1 million permutations in PLINK. Significant CNVs were confirmed with digital droplet polymerase chain reaction (ddPCR). Whole genome sequencing was performed to determine insertion location and breakpoints.

Results: Esotropia patients have similar rates and proportions of CNVs compared with controls but greater total length and average size of both deletions and duplications. Three recurrent rare duplications significantly (P = 1 {\texttimes} 10-6) increase the risk of esotropia: chromosome 2p11.2 (hg19, 2:87428677-87965359), spanning one long noncoding RNA (lncRNA) and two microRNAs (OR 14.16; 95\% confidence interval [CI] 5.4-38.1); chromosome 4p15.2 (hg19, 4:25554332-25577184), spanning one lncRNA (OR 11.1; 95\% CI 4.6-25.2); chromosome 10q11.22 (hg19, 10:47049547-47703870) spanning seven protein-coding genes, one lncRNA, and four pseudogenes (OR 8.96; 95\% CI 5.4-14.9). Overall, 114 cases (7\%) and only 28 controls (0.7\%) had one of the three rare duplications. No case nor control had more than one of these three duplications.

Conclusions: Rare CNVs are a source of genetic variation that contribute to the genetic risk for comitant esotropia, which is likely polygenic. Future research into the functional consequences of these recurrent duplications may shed light on the pathophysiology of esotropia.

}, keywords = {Case-Control Studies, DNA Copy Number Variations, Esotropia, Female, Gene Duplication, Gene Frequency, Genetic Predisposition to Disease, Genotyping Techniques, Humans, Infant, Male, Markov Chains, Polymerase Chain Reaction, Risk Factors}, issn = {1552-5783}, doi = {10.1167/iovs.61.10.22}, author = {Whitman, Mary C and Di Gioia, Silvio Alessandro and Chan, Wai-Man and Gelber, Alon and Pratt, Brandon M and Bell, Jessica L and Collins, Thomas E and Knowles, James A and Armoskus, Christopher and Pato, Michele and Pato, Carlos and Shaaban, Sherin and Staffieri, Sandra and MacKinnon, Sarah and Maconachie, Gail D E and Elder, James E and Traboulsi, Elias I and Gottlob, Irene and Mackey, David A and Hunter, David G and Engle, Elizabeth C} } @article {888, title = {Serum sphingolipids and incident diabetes in a US population with high diabetes burden: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {Am J Clin Nutr}, volume = {112}, year = {2020}, month = {2020 07 01}, pages = {57-65}, abstract = {

BACKGROUND: Genetic or pharmacological inhibition of de novo sphingolipid synthases prevented diabetes in animal studies.

OBJECTIVES: We sought to evaluate prospective associations of serum sphingolipids with incident diabetes in a population-based cohort.

METHODS: We included 2010 participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 y who were free of diabetes and other major chronic diseases at baseline (2008-2011). Metabolomic profiling of fasting serum was performed using a global, untargeted approach. A total of 43 sphingolipids were quantified and, considering subclasses and chemical structures of individual species, 6 sphingolipid scores were constructed. Diabetes status was assessed using standard procedures including blood tests. Multivariable survey Poisson regressions were applied to estimate RR and 95\% CI of incident diabetes associated with individual sphingolipids or sphingolipid scores.

RESULTS: There were 224 incident cases of diabetes identified during, on average, 6 y of follow-up. After adjustment for socioeconomic and lifestyle factors, a ceramide score (RR Q4 versus Q1~=~2.40; 95\% CI: 1.24, 4.65; P-trend~=~0.003) and a score of sphingomyelins with fully saturated sphingoid-fatty acid pairs (RR Q4 versus Q1~=~3.15; 95\% CI: 1.75, 5.67; P-trend~<0.001) both were positively associated with risk of diabetes, whereas scores of glycosylceramides, lactosylceramides, or other unsaturated sphingomyelins (even if having an SFA base) were not associated with risk of diabetes. After additional adjustment for numerous traditional risk factors (especially triglycerides), both associations were attenuated and only the saturated-sphingomyelin score remained associated with risk of diabetes (RR Q4 versus Q1~=~1.98; 95\% CI: 1.09, 3.59; P-trend~=~0.031).

CONCLUSIONS: Our findings suggest that a cluster of saturated sphingomyelins may be associated with elevated risk of diabetes beyond traditional risk factors, which needs to be verified in other population studies. This study was registered at clinicaltrials.gov as NCT02060344.

}, keywords = {Adolescent, Adult, Aged, Diabetes Mellitus, Female, Hispanic Americans, Humans, Male, Middle Aged, Prospective Studies, Risk Factors, Sphingolipids, United States, Young Adult}, issn = {1938-3207}, doi = {10.1093/ajcn/nqaa114}, author = {Chen, Guo-Chong and Chai, Jin Choul and Yu, Bing and Michelotti, Gregory A and Grove, Megan L and Fretts, Amanda M and Daviglus, Martha L and Garcia-Bedoya, Olga L and Thyagarajan, Bharat and Schneiderman, Neil and Cai, Jianwen and Kaplan, Robert C and Boerwinkle, Eric and Qi, Qibin} } @article {557, title = {Loss of function, missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts.}, journal = {Genet Epidemiol}, volume = {43}, year = {2019}, month = {2019 03}, pages = {215-226}, abstract = {

Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6\% of individuals. Rare or low-frequency missense variants were found in 16\% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes.

}, keywords = {Cohort Studies, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Heart Defects, Congenital, Humans, Introns, Loss of Function Mutation, Male, Mutation, Missense, Pedigree, Receptor, Notch1, Risk Factors, Ventricular Outflow Obstruction, Whole Exome Sequencing}, issn = {1098-2272}, doi = {10.1002/gepi.22176}, author = {Helle, Emmi and C{\'o}rdova-Palomera, Aldo and Ojala, Tiina and Saha, Priyanka and Potiny, Praneetha and Gustafsson, Stefan and Ingelsson, Erik and Bamshad, Michael and Nickerson, Deborah and Chong, Jessica X and Ashley, Euan and Priest, James R} } @article {441, title = {Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and~nephrocalcinosis.}, journal = {Kidney Int}, volume = {93}, year = {2018}, month = {2018 01}, pages = {204-213}, abstract = {

The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4\% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8\% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.

}, keywords = {Adolescent, Age of Onset, Child, Child, Preschool, Disease Progression, Female, Genetic Association Studies, Genetic Markers, Genetic Predisposition to Disease, Heredity, Humans, Infant, Male, Mutation, Nephrocalcinosis, Nephrolithiasis, Pedigree, Phenotype, Predictive Value of Tests, Prognosis, Risk Factors, Tomography, X-Ray Computed, Ultrasonography, Whole Exome Sequencing, Young Adult}, issn = {1523-1755}, doi = {10.1016/j.kint.2017.06.025}, author = {Daga, Ankana and Majmundar, Amar J and Braun, Daniela A and Gee, Heon Yung and Lawson, Jennifer A and Shril, Shirlee and Jobst-Schwan, Tilman and Vivante, Asaf and Schapiro, David and Tan, Weizhen and Warejko, Jillian K and Widmeier, Eugen and Nelson, Caleb P and Fathy, Hanan M and Gucev, Zoran and Soliman, Neveen A and Hashmi, Seema and Halbritter, Jan and Halty, Margarita and Kari, Jameela A and El-Desoky, Sherif and Ferguson, Michael A and Somers, Michael J G and Traum, Avram Z and Stein, Deborah R and Daouk, Ghaleb H and Rodig, Nancy M and Katz, Avi and Hanna, Christian and Schwaderer, Andrew L and Sayer, John A and Wassner, Ari J and Mane, Shrikant and Lifton, Richard P and Milosevic, Danko and Tasic, Velibor and Baum, Michelle A and Hildebrandt, Friedhelm} } @article {25, title = {Loss-of-function variants influence the human serum metabolome.}, journal = {Sci Adv}, volume = {2}, year = {2016}, month = {2016 Aug}, pages = {e1600800}, abstract = {

The metabolome is a collection of small molecules resulting from multiple cellular and biological processes that can act as biomarkers of disease, and African-Americans exhibit high levels of genetic diversity. Exome sequencing of a sample of deeply phenotyped African-Americans allowed us to analyze the effects of annotated loss-of-function (LoF) mutations on 308 serum metabolites measured by untargeted liquid and gas chromatography coupled with mass spectrometry. In an independent sample, we identified and replicated four genes harboring six LoF mutations that significantly affected five metabolites. These sites were related to a 19 to 45\% difference in geometric mean metabolite levels, with an average effect size of 25\%. We show that some of the affected metabolites are risk predictors or diagnostic biomarkers of disease and, using the principle of Mendelian randomization, are in the causal pathway of disease. For example, LoF mutations in SLCO1B1 elevate the levels of hexadecanedioate, a fatty acid significantly associated with increased blood pressure levels and risk of incident heart failure in both African-Americans and an independent sample of European-Americans. We show that SLCO1B1 LoF mutations significantly increase the risk of incident heart failure, thus implicating the metabolite in the causal pathway of disease. These results reveal new avenues into gene function and the understanding of disease etiology by integrating -omic technologies into a deeply phenotyped population study.

}, keywords = {Aged, Biomarkers, Black or African American, Exome, Female, Genetic Variation, Heart Failure, High-Throughput Nucleotide Sequencing, Humans, Hypertension, Liver-Specific Organic Anion Transporter 1, Male, Metabolome, Middle Aged, Mutation, Risk Factors, White People}, issn = {2375-2548}, doi = {10.1126/sciadv.1600800}, author = {Yu, Bing and Li, Alexander H and Metcalf, Ginger A and Muzny, Donna M and Morrison, Alanna C and White, Simon and Mosley, Thomas H and Gibbs, Richard A and Boerwinkle, Eric} } @article {640, title = {Characterization of a New DGKE Intronic Mutation in Genetically Unsolved Cases of Familial Atypical Hemolytic Uremic Syndrome.}, journal = {Clin J Am Soc Nephrol}, volume = {10}, year = {2015}, month = {2015 Jun 05}, pages = {1011-9}, abstract = {

BACKGROUND AND OBJECTIVES: Genetic and acquired abnormalities causing dysregulation of the complement alternative pathway contribute to atypical hemolytic uremic syndrome (aHUS), a rare disorder characterized by thrombocytopenia, nonimmune microangiopathic hemolytic anemia, and acute kidney failure. However, in a substantial proportion of patients the disease-associated alterations are still unknown.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: Whole-exome and whole-genome sequencing were performed in two unrelated families with infantile recessive aHUS. Sequencing of cDNA from affected individuals was used to test for the presence of aberrant mRNA species. Expression of mutant diacylglycerol kinase epsilon (DGKE) protein was evaluated with western blotting.

RESULTS: Whole-exome sequencing analysis with conventional variant filtering parameters did not reveal any obvious candidate mutation in the first family. The report of aHUS-associated mutations in DGKE, encoding DGKE, led to re-examination of the noncoding DGKE variants obtained from next-generation sequencing, allowing identification of a novel intronic DGKE mutation (c.888+40A>G) that segregated with disease. Sequencing of cDNA from affected individuals revealed aberrant forms of DGKE mRNA predicted to cause profound abnormalities in the protein catalytic site. By whole-genome sequencing, the same mutation was found in compound heterozygosity with a second nonsense DGKE mutation in all affected siblings of another unrelated family. Homozygous and compound heterozygous patients presented similar clinical features, including aHUS presentation in the first year of life, multiple relapsing episodes, and proteinuria, which are prototypical of DGKE-associated aHUS.

CONCLUSIONS: This is the first report of a mutation located beyond the exon-intron boundaries in aHUS. Intronic mutations such as these are underreported because conventional filtering parameters used to process next-generation sequencing data routinely exclude these regions from downstream analyses in both research and clinical settings. The results suggest that analysis of noncoding regions of aHUS-associated genes coupled with mRNA sequencing might provide a tool to explain genetically unsolved aHUS cases.

}, keywords = {Adolescent, Atypical Hemolytic Uremic Syndrome, Base Sequence, Blotting, Western, Child, Diacylglycerol Kinase, DNA Mutational Analysis, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heterozygote, Homozygote, Humans, Infant, Introns, Male, Molecular Sequence Data, Mutation, Phenotype, Predictive Value of Tests, Risk Factors}, issn = {1555-905X}, doi = {10.2215/CJN.08520814}, author = {Mele, Caterina and Lemaire, Mathieu and Iatropoulos, Paraskevas and Piras, Rossella and Bresin, Elena and Bettoni, Serena and Bick, David and Helbling, Daniel and Veith, Regan and Valoti, Elisabetta and Donadelli, Roberta and Murer, Luisa and Neunh{\"a}userer, Maria and Breno, Matteo and Fremeaux-Bacchi, Veronique and Lifton, Richard and Remuzzi, Giuseppe and Noris, Marina} } @article {222, title = {Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Oct 02}, pages = {345-59}, abstract = {

Most new mutations are observed to arise in fathers, and increasing paternal age positively correlates with the risk of new variants. Interestingly, new mutations in X-linked recessive disease show elevated familial recurrence rates. In male offspring, these mutations must be inherited from mothers. We previously developed a simulation model to consider parental mosaicism as a source of transmitted mutations. In this paper, we extend and formalize the model to provide analytical results and flexible formulas. The results implicate parent of origin and parental mosaicism as central variables in recurrence risk. Consistent with empirical data, our model predicts that more transmitted mutations arise in fathers and that this tendency increases as fathers age. Notably, the lack of expansion later in the male germline determines relatively lower variance in the proportion of mutants, which decreases with paternal age. Subsequently, observation of a transmitted mutation has less impact on the expected risk for future offspring. Conversely, for the female germline, which arrests after clonal expansion in early development, variance in the mutant proportion is higher, and observation of a transmitted mutation dramatically increases the expected risk of recurrence in another pregnancy. Parental somatic mosaicism considerably elevates risk for both parents. These findings have important implications for genetic counseling and for understanding patterns of recurrence in transmission genetics. We provide a convenient online tool and source code implementing our analytical results. These tools permit varying the underlying parameters that influence recurrence risk and could be useful for analyzing risk in diverse family structures.

}, keywords = {Adult, Aged, Aged, 80 and over, Chromosome Aberrations, DNA Copy Number Variations, Fathers, Female, Gametogenesis, Genetic Diseases, Inborn, Genomics, Germ Cells, Germ-Line Mutation, Humans, Inheritance Patterns, Male, Middle Aged, Models, Theoretical, Mosaicism, Mothers, Pregnancy, Recurrence, Risk Factors, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.08.010}, author = {Campbell, Ian M and Stewart, Jonathan R and James, Regis A and Lupski, James R and Stankiewicz, Pawe{\l} and Olofsson, Peter and Shaw, Chad A} }