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American Journal of Human Genetics

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https://www.readbyqxmd.com/read/29056226/a-dementia-associated-risk-variant-near-tmem106b-alters-chromatin-architecture-and-gene-expression
#1
Michael D Gallagher, Marijan Posavi, Peng Huang, Travis L Unger, Yosef Berlyand, Analise L Gruenewald, Alessandra Chesi, Elisabetta Manduchi, Andrew D Wells, Struan F A Grant, Gerd A Blobel, Christopher D Brown, Alice S Chen-Plotkin
Neurodegenerative diseases pose an extraordinary threat to the world's aging population, yet no disease-modifying therapies are available. Although genome-wide association studies (GWASs) have identified hundreds of risk loci for neurodegeneration, the mechanisms by which these loci influence disease risk are largely unknown. Here, we investigated the association between common genetic variants at the 7p21 locus and risk of the neurodegenerative disease frontotemporal lobar degeneration. We showed that variants associated with disease risk correlate with increased expression of the 7p21 gene TMEM106B and no other genes; co-localization analyses implicated a common causal variant underlying both association with disease and association with TMEM106B expression in lymphoblastoid cell lines and human brain...
October 16, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28985498/leveraging-multi-ethnic-evidence-for-risk-assessment-of-quantitative-traits-in-minority-populations
#2
Marc A Coram, Huaying Fang, Sophie I Candille, Themistocles L Assimes, Hua Tang
No abstract text is available yet for this article.
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28985497/dominant-mutations-in-grm1-cause-spinocerebellar-ataxia-type-44
#3
Lauren M Watson, Elizabeth Bamber, Ricardo Parolin Schnekenberg, Jonathan Williams, Conceição Bettencourt, Sandeep Jayawant, Jennifer Lickiss, Katherine Fawcett, Samuel Clokie, Yvonne Wallis, Penny Clouston, David Sims, Henry Houlden, Esther B E Becker, Andrea H Németh
No abstract text is available yet for this article.
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28985496/domino-using-machine-learning-to-predict-genes-associated-with-dominant-disorders
#4
Mathieu Quinodoz, Beryl Royer-Bertrand, Katarina Cisarova, Silvio Alessandro Di Gioia, Andrea Superti-Furga, Carlo Rivolta
In contrast to recessive conditions with biallelic inheritance, identification of dominant (monoallelic) mutations for Mendelian disorders is more difficult, because of the abundance of benign heterozygous variants that act as massive background noise (typically, in a 400:1 excess ratio). To reduce this overflow of false positives in next-generation sequencing (NGS) screens, we developed DOMINO, a tool assessing the likelihood for a gene to harbor dominant changes. Unlike commonly-used predictors of pathogenicity, DOMINO takes into consideration features that are the properties of genes, rather than of variants...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28985495/mendelian-randomization-analysis-identifies-cpg-sites-as-putative-mediators-for-genetic-influences-on-cardiovascular-disease-risk
#5
Tom G Richardson, Jie Zheng, George Davey Smith, Nicholas J Timpson, Tom R Gaunt, Caroline L Relton, Gibran Hemani
The extent to which genetic influences on cardiovascular disease risk are mediated by changes in DNA methylation levels has not been systematically explored. We developed an analytical framework that integrates genetic fine mapping and Mendelian randomization with epigenome-wide association studies to evaluate the causal relationships between methylation levels and 14 cardiovascular disease traits. We identified ten genetic loci known to influence proximal DNA methylation which were also associated with cardiovascular traits after multiple-testing correction...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28985494/the-contribution-of-neanderthals-to-phenotypic-variation-in-modern-humans
#6
Michael Dannemann, Janet Kelso
Assessing the genetic contribution of Neanderthals to non-disease phenotypes in modern humans has been difficult because of the absence of large cohorts for which common phenotype information is available. Using baseline phenotypes collected for 112,000 individuals by the UK Biobank, we can now elaborate on previous findings that identified associations between signatures of positive selection on Neanderthal DNA and various modern human traits but not any specific phenotypic consequences. Here, we show that Neanderthal DNA affects skin tone and hair color, height, sleeping patterns, mood, and smoking status in present-day Europeans...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28965849/biallelic-mutations-in-patl2-cause-female-infertility-characterized-by-oocyte-maturation-arrest
#7
Biaobang Chen, Zhihua Zhang, Xiaoxi Sun, Yanping Kuang, Xiaoyan Mao, Xueqian Wang, Zheng Yan, Bin Li, Yao Xu, Min Yu, Jing Fu, Jian Mu, Zhou Zhou, Qiaoli Li, Li Jin, Lin He, Qing Sang, Lei Wang
Oocyte maturation arrest results in female infertility, but the genetic determinants of human oocyte maturation arrest remain largely unknown. Previously, we identified TUBB8 mutations responsible for human oocyte maturation arrest, indicating the important role of genetic factors in the disorder. However, TUBB8 mutations account for only around 30% of individuals with oocyte maturation arrest; thus, the disorder is likely to involve other genetic factors that are as yet unknown. Here, we initially identified a homozygous nonsense mutation of PATL2 (c...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28965848/nested-inversion-polymorphisms-predispose-chromosome-22q11-2-to-meiotic-rearrangements
#8
Wolfram Demaerel, Matthew S Hestand, Elfi Vergaelen, Ann Swillen, Marcos López-Sánchez, Luis A Pérez-Jurado, Donna M McDonald-McGinn, Elaine Zackai, Beverly S Emanuel, Bernice E Morrow, Jeroen Breckpot, Koenraad Devriendt, Joris R Vermeesch
Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A-D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A-B 22q11.2 deletion carry inversions of LCR22B-D or LCR22C-D...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28965847/hypomorphic-recessive-variants-in-sufu-impair-the-sonic-hedgehog-pathway-and-cause-joubert-syndrome-with-cranio-facial-and-skeletal-defects
#9
Roberta De Mori, Marta Romani, Stefano D'Arrigo, Maha S Zaki, Elisa Lorefice, Silvia Tardivo, Tommaso Biagini, Valentina Stanley, Damir Musaev, Joel Fluss, Alessia Micalizzi, Sara Nuovo, Barbara Illi, Luisa Chiapparini, Lucia Di Marcotullio, Mahmoud Y Issa, Danila Anello, Antonella Casella, Monia Ginevrino, Autumn Sa'na Leggins, Susanne Roosing, Romina Alfonsi, Jessica Rosati, Rachel Schot, Grazia Maria Simonetta Mancini, Enrico Bertini, William B Dobyns, Tommaso Mazza, Joseph G Gleeson, Enza Maria Valente
The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Indeed, Sufu knock-out is lethal in mice, and recessive pathogenic variants of this gene have never been reported in humans...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28965846/fdxr-mutations-cause-sensorial-neuropathies-and-expand-the-spectrum-of-mitochondrial-fe-s-synthesis-diseases
#10
Antoine Paul, Anthony Drecourt, Floriane Petit, Delphine Dupin Deguine, Christelle Vasnier, Myriam Oufadem, Cécile Masson, Crystel Bonnet, Saber Masmoudi, Isabelle Mosnier, Laurence Mahieu, Didier Bouccara, Josseline Kaplan, Georges Challe, Christelle Domange, Fanny Mochel, Olivier Sterkers, Sylvie Gerber, Patrick Nitschke, Christine Bole-Feysot, Laurence Jonard, Souad Gherbi, Oriane Mercati, Ines Ben Aissa, Stanislas Lyonnet, Agnès Rötig, Agnès Delahodde, Sandrine Marlin
Hearing loss and visual impairment in childhood have mostly genetic origins, some of them being related to sensorial neuronal defects. Here, we report on eight subjects from four independent families affected by auditory neuropathy and optic atrophy. Whole-exome sequencing revealed biallelic mutations in FDXR in affected subjects of each family. FDXR encodes the mitochondrial ferredoxin reductase, the sole human ferredoxin reductase implicated in the biosynthesis of iron-sulfur clusters (ISCs) and in heme formation...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28965845/the-immune-signaling-adaptor-lat-contributes-to-the-neuroanatomical-phenotype-of-16p11-2-bp2-bp3-cnvs
#11
Maria Nicla Loviglio, Thomas Arbogast, Aia Elise Jønch, Stephan C Collins, Konstantin Popadin, Camille S Bonnet, Giuliana Giannuzzi, Anne M Maillard, Sébastien Jacquemont, Binnaz Yalcin, Nicholas Katsanis, Christelle Golzio, Alexandre Reymond
Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%-1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28965844/female-infertility-caused-by-mutations-in-the-oocyte-specific-translational-repressor-patl2
#12
Sateesh Maddirevula, Serdar Coskun, Saad Alhassan, Atif Elnour, Hessa S Alsaif, Niema Ibrahim, Firdous Abdulwahab, Stefan T Arold, Fowzan S Alkuraya
Infertility is a relatively common disorder of the reproductive system and remains unexplained in many cases. In vitro fertilization techniques have uncovered previously unrecognized infertility phenotypes, including oocyte maturation arrest, the molecular etiology of which remains largely unknown. We report two families affected by female-limited infertility caused by oocyte maturation failure. Positional mapping and whole-exome sequencing revealed two homozygous, likely deleterious variants in PATL2, each of which fully segregates with the phenotype within the respective family...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28942967/de-novo-mutations-in-ppp3ca-cause-severe-neurodevelopmental-disease-with-seizures
#13
Candace T Myers, Nicholas Stong, Emily I Mountier, Katherine L Helbig, Saskia Freytag, Joseph E Sullivan, Bruria Ben Zeev, Andreea Nissenkorn, Michal Tzadok, Gali Heimer, Deepali N Shinde, Arezoo Rezazadeh, Brigid M Regan, Karen L Oliver, Michelle E Ernst, Natalie C Lippa, Maureen S Mulhern, Zhong Ren, Annapurna Poduri, Danielle M Andrade, Lynne M Bird, Melanie Bahlo, Samuel F Berkovic, Daniel H Lowenstein, Ingrid E Scheffer, Lynette G Sadleir, David B Goldstein, Heather C Mefford, Erin L Heinzen
Exome sequencing has readily enabled the discovery of the genetic mutations responsible for a wide range of diseases. This success has been particularly remarkable in the severe epilepsies and other neurodevelopmental diseases for which rare, often de novo, mutations play a significant role in disease risk. Despite significant progress, the high genetic heterogeneity of these disorders often requires large sample sizes to identify a critical mass of individuals with disease-causing mutations in a single gene...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28942966/haploinsufficiency-of-the-chromatin-remodeler-bptf-causes-syndromic-developmental-and-speech-delay-postnatal-microcephaly-and-dysmorphic-features
#14
Paweł Stankiewicz, Tahir N Khan, Przemyslaw Szafranski, Leah Slattery, Haley Streff, Francesco Vetrini, Jonathan A Bernstein, Chester W Brown, Jill A Rosenfeld, Surya Rednam, Sarah Scollon, Katie L Bergstrom, Donald W Parsons, Sharon E Plon, Marta W Vieira, Caio R D C Quaio, Wagner A R Baratela, Johanna C Acosta Guio, Ruth Armstrong, Sarju G Mehta, Patrick Rump, Rolph Pfundt, Raymond Lewandowski, Erica M Fernandes, Deepali N Shinde, Sha Tang, Juliane Hoyer, Christiane Zweier, André Reis, Carlos A Bacino, Rui Xiao, Amy M Breman, Janice L Smith, Nicholas Katsanis, Bret Bostwick, Bernt Popp, Erica E Davis, Yaping Yang
Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28942965/biallelic-c1qbp-mutations-cause-severe-neonatal-childhood-or-later-onset-cardiomyopathy-associated-with-combined-respiratory-chain-deficiencies
#15
René G Feichtinger, Monika Oláhová, Yoshihito Kishita, Caterina Garone, Laura S Kremer, Mikako Yagi, Takeshi Uchiumi, Alexis A Jourdain, Kyle Thompson, Aaron R D'Souza, Robert Kopajtich, Charlotte L Alston, Johannes Koch, Wolfgang Sperl, Elisa Mastantuono, Tim M Strom, Saskia B Wortmann, Thomas Meitinger, Germaine Pierre, Patrick F Chinnery, Zofia M Chrzanowska-Lightowlers, Robert N Lightowlers, Salvatore DiMauro, Sarah E Calvo, Vamsi K Mootha, Maurizio Moggio, Monica Sciacco, Giacomo P Comi, Dario Ronchi, Kei Murayama, Akira Ohtake, Pedro Rebelo-Guiomar, Masakazu Kohda, Dongchon Kang, Johannes A Mayr, Robert W Taylor, Yasushi Okazaki, Michal Minczuk, Holger Prokisch
Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28942964/fine-mapping-and-functional-analysis-reveal-a-role-of-slc22a1-in-acylcarnitine-transport
#16
Hye In Kim, Johannes Raffler, Wenyun Lu, Jung-Jin Lee, Deepti Abbey, Danish Saleheen, Joshua D Rabinowitz, Michael J Bennett, Nicholas J Hand, Christopher Brown, Daniel J Rader
Genome-wide association studies have identified a signal at the SLC22A1 locus for serum acylcarnitines, intermediate metabolites of mitochondrial oxidation whose plasma levels associate with metabolic diseases. Here, we refined the association signal, performed conditional analyses, and examined the linkage structure to find coding variants of SLC22A1 that mediate independent association signals at the locus. We also employed allele-specific expression analysis to find potential regulatory variants of SLC22A1 and demonstrated the effect of one variant on the splicing of SLC22A1...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28942963/prospects-of-fine-mapping-trait-associated-genomic-regions-by-using-summary-statistics-from-genome-wide-association-studies
#17
Christian Benner, Aki S Havulinna, Marjo-Riitta Järvelin, Veikko Salomaa, Samuli Ripatti, Matti Pirinen
During the past few years, various novel statistical methods have been developed for fine-mapping with the use of summary statistics from genome-wide association studies (GWASs). Although these approaches require information about the linkage disequilibrium (LD) between variants, there has not been a comprehensive evaluation of how estimation of the LD structure from reference genotype panels performs in comparison with that from the original individual-level GWAS data. Using population genotype data from Finland and the UK Biobank, we show here that a reference panel of 1,000 individuals from the target population is adequate for a GWAS cohort of up to 10,000 individuals, whereas smaller panels, such as those from the 1000 Genomes Project, should be avoided...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28886345/rac1-missense-mutations-in-developmental-disorders-with-diverse-phenotypes
#18
Margot R F Reijnders, Nurhuda M Ansor, Maria Kousi, Wyatt W Yue, Perciliz L Tan, Katie Clarkson, Jill Clayton-Smith, Ken Corning, Julie R Jones, Wayne W K Lam, Grazia M S Mancini, Carlo Marcelis, Shehla Mohammed, Rolph Pfundt, Maian Roifman, Ronald Cohn, David Chitayat, Tom H Millard, Nicholas Katsanis, Han G Brunner, Siddharth Banka
RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p...
September 7, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28886344/a-recurrent-missense-mutation-in-zp3-causes-empty-follicle-syndrome-and-female-infertility
#19
Tailai Chen, Yuehong Bian, Xiaoman Liu, Shigang Zhao, Keliang Wu, Lei Yan, Mei Li, Zhenglin Yang, Hongbin Liu, Han Zhao, Zi-Jiang Chen
Empty follicle syndrome (EFS) is defined as the failure to aspirate oocytes from mature ovarian follicles during in vitro fertilization. Except for some cases caused by pharmacological or iatrogenic problems, the etiology of EFS remains enigmatic. In the present study, we describe a large family with a dominant inheritance pattern of female infertility characterized by recurrent EFS. Genome-wide linkage analyses and whole-exome sequencing revealed a paternally transmitted heterozygous missense mutation of c...
September 7, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28886343/dominant-mutations-in-grm1-cause-spinocerebellar-ataxia-type-44
#20
Lauren M Watson, Elizabeth Bamber, Ricardo Parolin Schnekenberg, Jonathan Williams, Conceição Bettencourt, Jennifer Lickiss, Sandeep Jayawant, Katherine Fawcett, Samuel Clokie, Yvonne Wallis, Penny Clouston, David Sims, Henry Houlden, Esther B E Becker, Andrea H Németh
The metabotropic glutamate receptor 1 (mGluR1) is abundantly expressed in the mammalian central nervous system, where it regulates intracellular calcium homeostasis in response to excitatory signaling. Here, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different families to adult-onset cerebellar ataxia, and a de novo truncation mutation resulting in a dominant-negative effect that is associated with juvenile-onset ataxia and intellectual disability...
September 7, 2017: American Journal of Human Genetics
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