European Review for Medical and Pharmacological Sciences 2016; 20: 3672-3678 Novel information on the genetic factors involved in the development of diseases

S.M. KOTELEVETS1, Z.M. GALEEVA2, Z.B. KARAKOTOVA1, S.A. CHEKH3

1Department of Therapy, Medical Institute, North Caucasus State Academy of Humanities and Technology, Cherkessk, Russian Federation 2Department of Therapy, Kazan State Medical Academy, Kazan, Russian Federation 3Department of Information Systems, North Caucasus State Academy of Humanities and Technology, Cherkessk, Russian Federation

Abstract. Nowadays full-genome sequenc- firmed, a time trial begins in order to track down ing allows achieving revolutionary progress in the source of the infection and prevent its spread. the modern medicine. As the result of a huge The method of full-genome sequencing allowed work on the study of the and tracking down this episode in a couple of days1. based on the results obtained, one can con- clude that the single nucleotide polymorphisms Using the new technique, scientists were able are the reasons of the vast majority of non-com- to identify a transforming normal cells into municable diseases as well as the diseases oth- cancer cells. A team of researchers from the Case er than injuries and poisoning, i.e. the diseas- Western Reserve University School of Medicine es where the cause is not obvious. To clarify the has identified a gene, the overexpression of which role of single nucleotide polymorphism in the makes normal cells behave like cancer cells, by occurrence of atrophic gastritis, it is required to using the new method of verified insertional muta- perform full-genome sequencing and human ge- nome scanning with a simultaneous mass sero- genesis. The discovery of FAM83B gene was made logical screening of atrophic gastritis. As a re- using the model of breast cancer cells. During the sult, it will be possible to establish which sin- observation of tumor formation, researchers were gle nucleotide polymorphism is responsible for able to identify gene overexpression that turns mild, moderate, and severe mucosal atrophy in normal cells into cancer cells, causing indepen- the antrum and the body of the stomach. Sero- dent cell growth of mammary epithelial cells. The logical screening of mild, moderate, and severe mucosal atrophy in the antrum and the body of discovery of new oncogenes provides opportuni- the stomach can be made using GastroPanel. ties for the development of new drugs aimed at inhibiting the FAM83A gene in the patients having Key Words aggressive forms of cancer, which are too compli- Atrophic gastritis, Serological screening, Single nu- cated for conventional treatment2. cleotide polymorphism, Population.

Materials and Methods

Introduction Singapore researchers have identified three new genetic polymorphisms associated with primary Nowadays full-genome sequencing allows angle-closure glaucoma. Scientists from more than achieving revolutionary progress in the mod- thirty research sites have conducted a genome-wide ern medicine. This technology helped specialists analysis of the DNA samples from five databases from the National Human Genome Research In- collected in Asia [1854 patients with primary an- stitute in the US to cope with hospital infection. gle-closure glaucoma, and 9608 subjects in the con- The method of bacterial genome sequencing suc- trol group]. As the result three previously unknown cessfully allowed us to track nosocomial pneu- loci on 8q associated with high risk of monia episodes. Gram-negative bacteria Kleb- developing primary angle-closure glaucoma were siella pneumoniae is the main cause of hospital identified: rs11024102 in PLEKHA7 gene, infections, particularly among the immunocom- rs3753841 locus in COL11A1 gene and rs1015213 promised patients. When the episode is con- locus located between PCMTD1 and ST18 genes3.

3672 Corresponding Author: Sergey M. Kotelevets; e-mail: [email protected] Novel information on the genetic factors involved in the development of diseases

The international team of researchers led by with the disease. The newly identified regions Janusz Jankowski, Professor of the Blizard In- of the genome, presumably associated with the stitute of Cell and Molecular Science at Queen disease, have been replicated at 13,347 stroke Mary, University of London studied the genomic patients and 29,083 study participants without variants in 1852 British and other people suffer- the disease. Previously discovered genetic asso- ing from Barrett’s esophagus and compared their ciations in the cardioembolic stroke have been data with about 6,000 people that did not have confirmed for PITX2 and ZFHX3 , as well the disease. As a result, they found two genetic as associations of stroke caused by blockage of determinants associated with this disorder. Two the large vessels in 9p21 locus and HDAC9 gene. single nucleotide polymorphisms in the chromo- In addition, it was confirmed that all the asso- somal regions 6r21 and 16q24 showed correlation ciations are typical for specific stroke subtypes. with Barrett’s esophagus. Based on the results Conditional analysis of the three areas in which of this study, scientists will be able to develop a associations were complied with the criterion of system of genetic screening of the 35% of the UK genome-wide significance [PITX2, ZFHX3 and population who complain of acid reflux. In one of HDAC9] showed that all the important areas in each 5 subjects, it will be possible to predispose each region could be associated with one haplo- Barrett’s esophagus and prevent the development type, which increases the risk of disease. 12 new of esophageal cancer4. potentially significant loci were also revealed. A large group of authors conducted the Ge- However, none of these new associations could be nome-Wide Association Study (GWAS). It en- replicated in the cohort of the subjects, in whom rolled 7410 prospectively and retrospectively se- the genome was replicated. These results indicate lected patients with severe osteoarthritis, as well that despite the possibility of the gene polymor- as 11,009 people without osteoarthritis living in phisms detection in the patients with ischemic the UK who are not their relatives. We replicated stroke (compared with the control group) all the the most likely areas of the genetic material in confirmed associations were typical for specific independent samples of 7473 patients with osteo- stroke subtypes. This result allows us to make arthritis and 42,938 people without the disease, two conclusions. Firstly, to maximize the success received during a number of studies conducted of genetic studies of ischemic stroke, one should in Iceland, Estonia, Netherlands and the UK. select the stroke subtypes. Secondly, different All the patients suffering from osteoarthritis and subtypes of stroke are apparently caused by vari- participants of the study without this disease were ous genetic pathophysiological mechanisms6. the Europeans. The strongest association with os- The purpose of the study conducted by the teoarthritis was found for rs6976 gene variant on members of the Consortium of Psychiatric Ge- being in complete disequilibrium nomics was to identify the specific genetic vari- linkage with rs11177 gene variant. This single ations underlying common genetic mechanisms nucleotide polymorphism [SNP] causes missense of five diseases: Autism Spectrum Disorder, At- polymorphism in GNL3 gene responsible for tention Deficit Hyperactivity Disorder, Bipolar nucleostemin production. Elevated nucleostemin Disorder, Major Depressive Disorder and Schizo- level was observed in chondrocytes of patients phrenia. Full-genome analysis of single nucleo- with osteoarthritis during the functional studies. tide polymorphism was performed among 33,332 Another important site located in the FTO gene patients with these five diseases and among was involved in the regulation of body weight, 27,888 healthy subjects from the control group which is a significant risk factor of osteoarthritis [all the study participants were the Europeans]. In development5. order to describe the effect of individual alleles in Meta-analysis of 15 cohorts of patients with the development of each disease, we used multi- ischemic stroke was conducted. It included a nomial logistic regression in order to identify the total number of 12,389 patients and 62,004 heath model that reflects the relationship between geno- subjects without the disease being in the control type and phenotype in the optimal way. Influence group [all the study participants were the Euro- of the loci corresponding to the genome-wide sig- peans]. For the associations that conform to the nificance and previously identified criteria among relevant criterion of genome-wide significance the patients with bipolar disorder and schizophre- according to the METASTROKE study, addition- nia on the development of the mentioned mental al analysis based on the single nucleotide poly- illnesses was studied. In addition, a risk analysis morphism was conducted in each area associated of polygenic diseases was performed in order to

3673 S.M. Kotelevets, Z.M. Galeeva, Z.B. Karakotova, S.A. Chekh study the impact of a number of common genetic presence of the specific subtype of FKBP5 gene. polymorphisms on these mental illnesses. The FKBP5 gene determines the effectiveness of the analysis of signaling cascades was performed in body’s response to stressful stimuli and controls order to identify biological links underlying com- the entire system of the stress hormones. Severe mon genetic mechanisms of the development of stressful event occurred in the childhood leads to all five diseases. Also in the postmortem samples epigenetic changes in the structure of gene and of the brain tissue the expressive representation dysregulation of the stress hormones. However, of quantitative trait loci [eQTL] was analyzed in epigenetic changes in DNA do not occur in all the order to identify the prevalence of the present- individuals suffered serious childhood trauma, ed SNP in regulatory regions among the SNPs but only in those who have genetic predisposition associated with the occurrence of the studied to a particular violation in FKBP5 gene. This mental disorders. The primary analysis revealed study contributes to a better understanding of four SNPs loci exceeding the genome-wide sig- the mechanisms of psychiatric diseases, as well nificance level: in chromosomal regions 3p21 as awareness of the differences between innate and 10q24, as well in the genes encoding two and acquired factors leading to this pathology. It subunits of voltage-gated L-type calcium chan- is expected that the results of this research will nel [and CACNB2]. Analysis of the selected help to choose correct methods of treatment for models confirmed the impact of these loci on patients who experienced a severe stress situation the development of several diseases. Loci that in their childhood7,8. were previously associated with schizophrenia Reitz et al9 conducted a meta-analysis of data or bipolar disorder had different diagnostic spec- obtained from a survey that enrolled the Afri- ificity. Associations between risk assessments can-Americans and found that Alzheimer’s dis- of polygenic diseases and the studied disorders ease was often associated with the SNPs in AB- were identified, especially those emerging in the CA7 and other genes that were common in the adulthood. Signal cascades analysis confirmed Europeans suffering from Alzheimer’s disease. that calcium channels genes are involved in the Majounie et al10 also confirmed the association development of all five diseases. Finally, the of neurological disorders genes with amyotrophic analysis of the postmortem brain tissue samples lateral sclerosis (ALS). revealed that among the SNPs associated with the It was possible to establish an association development of the studied psychiatric disorders between the mutations in genes associated with eQTL markers were very common. The findings prolongation of QT interval and previously un- obtained suggest a strong association between explained cases of fetal death. Intrauterine fetal the individual SNPs and the number of mental death occurs in one of every 160 pregnancies. illnesses that occur among adults or children. In At the same time, 25-40% of cases of fetal death particular, calcium channel gene variations seem cannot be explained by such factors as chromo- to have pleiotropic effects, causing the occur- somal abnormalities, fetal infection, fetoplacental rence of various mental disorders. The obtained insufficiency, or comorbidities of the mother. data can be used to transit from the descripting A recent study conducted by the Mayo Clinic system of psychiatric syndromes to the nosologi- explained some of the fetal deaths (previously cal classification of mental illness based on their considered idiopathic) by mutations in the genes causes. In addition, the researchers from the Max responsible for the proper function of ion chan- Planck Institute of Psychiatry in Munich have nels and cells associated with prolongation of found that the trauma happened in childhood lead the QT interval. In order to evaluate the effect of to the change in the regulation of DNA methyl- mutations of genes associated with QT interval ation. This violates the mechanism of the stress prolongation syndrome on the fetal death, the re- hormones production. The individuals having searchers have analyzed genetic material received traumatic experience in the childhood were sig- from 91 cases of intrauterine death resulted from nificantly more likely to develop depression and the unknown factors. The average gestational age anxiety disorders during their life. In the process at the time of fetal death was 26.3 weeks. The use of the DNA analysis of 2000 African-Americans of liquid chromatography showed that three spe- often experiencing serious traumatic events in cific missense mutations in KCNQ1 and KCNQ2 their childhood and adulthood, it was noted that genes (associated with prolonged QT interval the development of posttraumatic stress disorder syndrome) were present in 3 studied fetuses. among these patients was associated with the Thus, the frequency of these mutations among

3674 Novel information on the genetic factors involved in the development of diseases the deceased fetuses was 3.3%. The frequency mal genetic variant. [Dominant genetic variants of heterozygotes according to the mutations in are those that can cause symptoms in the pres- the general population is 0.05%. In addition, ence of even a single copy of the genome]. Clin- researchers have discovered 5 rare mutations of ical manifestations of genetic diseases in these SCN5A gene, allegedly causing poly arrhythmic people were either mild or completely absent. violations in heart. Mutations associated with the The researchers suggested that in case of their syndrome of prolonged QT are also recorded in absence clinical symptoms may appear in the 10% children deceased from the sudden infant later stages of life. According to the authors, their death syndrome. Such significant difference in results made it clear that even in normal healthy the incidence of the syndrome of prolonged QT organisms many can be represented by interval among the cases of embryo fetal death as abnormal or even completely inactivated forms well as among the children with the syndrome of without any significant damage to the health. sudden infant death and adult population substan- It is extremely difficult to predict the clinical tiates the necessity for screening pregnant women effects of the presence of nucleotide polymor- for the presence of specific mutations11. phism in each particular case. The only way to The researchers at the Cardiff University and alleviate this problem is the further development the Sanger Institute in Cambridge have found that of databases containing information associated every healthy person is a carrier of about 400 nu- with various diseases of genetic variants. Such cleotide polymorphisms, representing a potential databases have been developed in the past two threat to health, and 2 nucleotide polymorphisms decades. However, the work on their creation is directly associated with diseases. They showed far from the end. In general, abnormal genetic that 1 out of every 10 participants in the study variants are quite rare and in many populations, could develop a genetic disease as the result of their search had not been performed. The ge- carrying of such nucleotide polymorphisms. It is netic material used in this study was collected not the first decade when genetic specialists are anonymously, so the participants cannot get any aware of the fact that every human gene contains information about the risk of development of cer- pathological variants of DNA that have almost no tain genetic abnormalities. Such situations cause effect on health. The authors made the first quan- growing concern in the researchers because of titative assessment of the content of such variants their ethical ambiguity12. in the genomes of healthy individuals. For doing this, they compared the information contained in the two databases: full-genome DNA sequences Results and Discussion of 179 participants of the pilot project involving 1000 genomes with a low degree of probability of The project resulted in a multinational con- any obvious symptoms of the genetic diseases at sortium of researchers called “1000 Genomes” the time of blood withdraw for the DNA analysis; and the standard distribution of the SNPs has and the detailed catalog of mutations associated been defined. As a part of this work, we have with various human diseases described in the sequenced the genomes of 1092 representatives in scientific literature. Figure of 400 will likely 14 different populations. The ultimate goal of this increase along with the increase in the efficiency five-year study was to provide biologists and cli- of the methods for the SNPs studying. Conduc- nicians with the information that will help them tion of such works raises ethical issues related to to understand the spectrum of normal nucleotide the anonymity of participation in genetic studies polymorphisms that make up human genome. and casual findings. In many cases, pathological This in its turn will interpret the information or damaged genes represent “recessive” genetic contained in the genome in a wider context. variants which have no influence on the health The analyzed populations were selected based on of the carrier as they are presented in combina- their migration history and genetic relationship tion with a normal copy of the gene. Destructive with each other. Healthy donors, that were not effects of recessive genetic variants occur only relatives, were randomly selected in each popu- if there are two pathological genes - one in each lation. Cells lines precursors suitable for endless pair of . However, as it turned out, storage and reproduction were isolated from the one out of every 10 participants in the study is a collected blood samples. DNA was sequenced carrier of two copies of the recessive pathological using isolated cells and the data obtained was changes of the same gene or a dominant abnor- listed in public databases. After the sequence of

3675 S.M. Kotelevets, Z.M. Galeeva, Z.B. Karakotova, S.A. Chekh the first sequenced human genome was published ect was completed in 2008. It was planned as a in 2003, it became clear that contrary to the preliminary study of the genomes sequenced for traditional view, 98.5% of human genetic mate- the second phase of the project and demonstrated rial does not encode proteins. The scientists are the feasibility of the search of genetic markers of currently familiar with the function of a number various diseases. As a part of the final phase of of non-coding regions of the genome, but most the project, it is planned to sequence the genomes of the genetic sequence is still an enigma. There of another 1,500 people from 11 previously un- is a reason to believe that at least part of genetic covered populations. The project has involved material is responsible for variability and sus- more than 100 scientists from 111 research sites ceptibility to disease. Nucleotide polymorphisms all over the world13. identified in the representatives of the analyzed As a result of a huge work on the study of the populations were divided into the categories de- human genome and based on the results obtained pending on the frequency of occurrence. Variants it can be concluded that single nucleotide poly- detected in more than 5% of the samples were morphisms are the reason of the vast majority considered as common, in 0.5-5% of the samples of non-communicable diseases. And of course, – as less common, and in less than 0.5% of the the role of prevention of conditions that can be samples – as rare. 14 analyzed populations were avoided becomes apparent for timely prophylactic divided into 4 groups: the Europeans, Africans, measures. East Asians, and Americans. As was expected by This finding allows Juengst E.T., Flatt M.A., the researchers, the majority of common variants Settersten R.A. Jr. to make a conclusion that were previously identified, with a little variation genetic medicine can cause patients to change of their frequency depending on the origin of the their lifestyle. It is possible that patients will be- group. In contrast, 58% and 87% of less common come more responsible for their own health. The variants were described for the first time. In introduction of genetic medicine could markedly some cases, rare variants occurred in a particular change the standard approach to the treatment. population twice more common than in the wid- Its widespread acceptance will lead to the fact er group, including this population. A different that patients will be able to self-monitor their number of rare variants was identified in different own health. Gene diagnostics allows assessing populations. Their greatest variety was typical the pharmacogenomic information, which is the for the Spanish, Finnish and African-American reaction of the patient to a particular therapy and populations. It was a total surprise that in case genetic susceptibility, showing the probability in of some rare variants the study participants were which patient is exposed to the disease. Support- healthy carriers of 130-400 gene variants chang- ers of genomic medicine (from private research ing the structure of molecules; 10-20 gene centers to the National Institute of Health) are variants depriving the ability of proteins encoded interested to deliver this information to patients. by them to perform their essential function; 2-5 Although the question of how the results of gene gene variants that violate protein function; and diagnostics can affect patient and his attitude 1-2 variants associated with malignant tumors. to their own health remains open. Pharmacog- This means that healthy people, regardless of enomic information can make people follow your ethnic origin are the carriers of approximately the doctor’s instructions more closely, as the results same amount of rare gene variants being harmful of the molecular analysis can make the prescrip- to health. tions more accurate and authoritative. Genetic According to Aravinda Chakravarti, Professor medicine allows revealing a significantly larger from the Johns Hopkins University and one of amount of risks for the patient, which is a key fac- the study leaders, there are several factors that tor in the treatment of diseases and general health ensure the survival of people despite the presence assessment. The benefits of genetic susceptibility of so many errors in their genomes. One of the studies can be misinterpreted. Nowadays the use mechanisms is that, despite the presence of two of genomic data allows only calculating the risk variants of each gene, our body needs only one of some disease in the group of people. Often, normal gene variant for the normal life. Another the division into groups by ethnic or racial fac- factor is the presence of “reserve” genes in our tors does not allow determining the likelihood of genome. In some cases, these “reserve” genes developing the disease in every particular patient can compensate the effects of a nonfunctional being in the risk group. Also, we can note that the protein. The first phase of “1000 Genomes” proj- development of the disease is often determined

3676 Novel information on the genetic factors involved in the development of diseases by a person’s lifestyle. The role of the physician References is to point to the potential risks while much of the responsibility for the occurrence of the disease is 1) Snitkin ES, Zelazny AM, Thomas PJ, Stock F; NISC on the patient. Thus, the use of the data of gene Comparative Sequencing Program Group, Henderson therapy in medical practice leads to “delegation DK, Palmore TN, Segre JA. Tracking a hospi- of powers” from the physician to the patient. Ex- tal outbreak of carbapenem-resistant Klebsiella perts point out that further studies are necessary pneumoniae with whole-genome sequencing. Sci Transl Med 2012; 4: 148ra116. to determine whether the data of gene diagnostic 2) Cipriano R, Graham J, Miskimen KL, Bryson BL, can encourage patients to adopt a healthier life- Bruntz RC, Scott SA, Brown HA, Stark GR, Jackson style14. Recent advances in genetics suggest that MW. FAM83B mediates EGFR- and RAS-driven single nucleotide polymorphisms can cause any oncogenic transformation. J Clin Invest 2012; 122: diseases other than infectious diseases, as well as 3197-3210. 3) Vithana EN, Khor CC, Qiao C. Genome-wide asso- those caused by obvious reasons [trauma, poison- ciation analyses identify three new susceptibility ing, etc.]. However, the reasons of single nucleo- loci for primary angle closure glaucoma. Nat Gen- tide polymorphism are not clear. This individual et 2012; 44: 1142-1146. SNPs could be inherited from parents (i.e. it has 4) Su Z, Gay LJ, Strange A, Palles C, Band G, Whiteman DC, Lescai F, Langford C, Nanji M, Edkins S, van der an inherited nature), it could also appeared in an Winkel A, Levine D, Sasieni P, Bellenguez C, Howarth individual’s life (i.e. it has an acquired character). K, Freeman C, Trudgill N, Tucker AT, Pirinen M, Pep- In order to clarify this, one needs to conduct spe- pelenbosch MP, van der Laan LJ, Kuipers EJ, Drenth cial studies to identify a particular single nucleo- JP, Peters WH, Reynolds JV, Kelleher DP, McManus tide polymorphism in the genome simultaneously R, Grabsch H, Prenen H, Bisschops R, Krishnadath K, Siersema PD, van Baal JW, Middleton M, Petty R, in healthy and diseased cells of the affected organ Gillies R, Burch N, Bhandari P, Paterson S, Edwards in particular human diseases, such as Barrett’s C, Penman I, Vaidya K, Ang Y, Murray I, Patel P, Ye W, esophagus or breast cancer. If such nucleotide Mullins P, Wu AH, Bird NC, Dallal H, Shaheen NJ, polymorphisms are detected in diseased cells and Murray LJ, Koss K, Bernstein L, Romero Y, Hardie LJ, cells still being normal, as well as in normal cells Zhang R, Winter H, Corley DA, Panter S, Risch HA, Reid BJ, Sargeant I, Gammon MD, Smart H, Dhar A, of other organs and tissues of the individual, it is McMurtry H, Ali H, Liu G, Casson AG, Chow WH, likely that nucleotide polymorphism is inherited. Rutter M, Tawil A, Morris D, Nwokolo C, Isaacs P, If the nucleotide polymorphism is detected only Rodgers C, Ragunath K, MacDonald C, Haigh C, in the affected cells of the patient’s body while it Monk D, Davies G, Wajed S, Johnston D, Gibbons M, is not detected in other cells of the individual, we Cullen S, Church N, Langley R, Griffin M, Alderson D, Deloukas P, Hunt SE, Gray E, Dronov S, Potter can say that nucleotide polymorphism possibly SC, Tashakkori-Ghanbaria A, Anderson M, Brooks C, has an acquired character. Blackwell JM, Bramon E, Brown MA, Casas JP, Cor- vin A, Duncanson A, Markus HS, Mathew CG, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Trembath RC, Conclusions Viswanathan AC, Wood N, Trynka G, Wijmenga C, Cazier JB, Atherfold P, Nicholson AM, Gellatly NL, Glancy D, Cooper SC, Cunningham D, Lind T, Hapeshi To clarify the role of single nucleotide poly- J, Ferry D, Rathbone B, Brown J, Love S, Attwood S, morphism in the occurrence of atrophic gastritis, MacGregor S, Watson P, Sanders S, Ek W, Harrison it is required to perform the full-genome sequenc- RF, Moayyedi P, de Caestecker J, Barr H, Stupka E, ing of the human genome with a mass simulta- Vaughan TL, Peltonen L, Spencer CC, Tomlinson I, Donnelly P, Jankowski JA, Esophageal Adenocarcinoma neous serological screening of atrophic gastritis. Genetics Consortium, Wellcome Trust Case Control As a result, it will be possible to establish which Consortium 2. Common variants at the MHC locus single nucleotide polymorphism can cause mild, and at chromosome 16q24.1 predispose to Bar- moderate, and severe mucosal atrophy in the rett’s esophagus. Nat Genet 2012; 44: 1131-1136. antrum and the body of the stomach. Serological 5) Zeggini E, Panoutsopoulou K, Southam L, Rayner NW, Day-Williams AG, Lopes MC, Boraska V, Esko screening of mild, moderate, and severe mucosal T, Evangelou E, Hoffman A, Houwing-Duistermaat atrophy in the antrum and the body of the stom- JJ, Ingvarsson T, Jonsdottir I, Jonnson H, Kerkhof 15-19 ach can be performed using GastroPanel . HJ, Kloppenburg M, Bos SD, Mangino M, Metrustry S, Slagboom PE, Thorleifsson G, Raine EV, Ratnayake M, Ricketts M, Beazley C, Blackburn H, Bumpstead S, Elliott KS, Hunt SE, Potter SC, Shin SY, Yadav VK, Conflict of Interests Zhai G, Sherburn K, Dixon K, Arden E, Aslam N, The Authors declare that they have no potential conflict of Battley PK, Carluke I, Doherty S, Gordon A, Joseph interests. J, Keen R, Koller NC, Mitchell S, O’Neill F, Paling E,

3677 S.M. Kotelevets, Z.M. Galeeva, Z.B. Karakotova, S.A. Chekh

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