Genomic Architecture of Schizophrenia Across Diverse Genetic Isolates

164 Pages·2016·3.89 MB·English

Kazima Bulayeva · Oleg Bulayev
Stephen Glatt
Genomic
Architecture of
Schizophrenia
Across Diverse
Genetic Isolates
A Study of Dagestan Populations
Genomic Architecture of Schizophrenia Across
Diverse Genetic Isolates
[email protected]
Kazima Bulayeva (cid:129) Oleg Bulayev (cid:129) Stephen Glatt
Genomic Architecture of
Schizophrenia Across
Diverse Genetic Isolates
A Study of Dagestan Populations
[email protected]
KazimaBulayeva OlegBulayev
RussianAcademyofSciences RussianAcademyofSciences
Moscow,Russia Moscow,Russia
StephenGlatt
DepartmentofPsychiatry
andBehavioralSciences
SUNYUpstateMedicalUniversity
Syracuse,NewYork
USA
ISBN978-3-319-31962-9 ISBN978-3-319-31964-3 (eBook)
DOI10.1007/978-3-319-31964-3
LibraryofCongressControlNumber:2016939944
©SpringerInternationalPublishingSwitzerland2016
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Oneofremotehighlandgenetic isolatewherewe hadourstudy
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Foreword
Psychiatric disorders are among the world’s most complex and least understood
ailments; yet, relative to other medical disorders, they cause a disproportionate
shareofsuffering.Theauthorsofthisvolume,Dr.KazimaBulayevaandherson,
Dr.OlegBulayev,havededicatednotjusttheirscientificcareers,buttheirlives,to
combatting these disorders by increasing our understanding of their causes. Their
workisthetrueembodimentofgeneticepidemiology,definedbyNewtonMorton
as“asciencewhichdeals withtheetiology,distribution,andcontrolofdiseasein
groupsofrelativesandwithinheritedcausesofdiseaseinpopulations.”1
Thisvolumerepresentsafittingcompilationofdecadesoflabor,atruelaborof
lovethathaspersevereddespitemanyobstacles,fromthefinancialtothepolitical,
tothephysicalchallengesofnavigatingthemountainousterrainoftheCaucasus,to
the social and cultural difficulties of developing and nurturing deep interpersonal
relationshipswiththeindigenouspeopleinthehighlandsofDagestan.Throughthis
effort, Drs. Bulayeva and Bulayev have been able to develop a truly unique
relationship with their subjects and a matchless, singular research program. In
this monograph, you, the reader, will be immersed into the scientific workflow of
Drs. Bulayeva and Bulayev, and you will feel the intensity of their painstaking
effort to dissect the genetic underpinnings of mental disorders that aggregate in
distinctethnicisolates.Althoughtechnicaladvancesinthefieldhaveusheredinan
era of personal and precision medicine, Drs. Bulayeva and Bulayev show us the
powerandthepromiseofcarefulascertainment,richclinicalcharacterization,and
traditionalfamily-basedgeneticanalysismethodsfordiscoveringgenomiclocithat
mayharborrisk-conferringgenesformentaldisorders.Thisworkisatestimonial,a
1Morton,N.E.(1982).Outlineofgeneticepidemiology.NewYork:Karger.ISBN3-8055-2269-X.
vii
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viii Foreword
tutorial even, on the rewards to be reaped through the careful application of
fundamentalmethodsofgeneticepidemiologyandofsoundscience.
Syracuse,NY,USA StephenJ.Glatt
February10,2016
[email protected]
Preface
Thestudyofgenetics ofcomplexdiseasesisoneofthemain priorities ofmodern
genetics,asthesediseasesaretheleadingcauseofprematuredeathanddisability.
Mental diseases—sсhizophrenia, depression, bipolar disorders, and so on—are
among the most severe complex diseasesfor both patients and society. Currently,
the rate of affectation by these mental diseases is increasing in most countries.
Thousandsofscientistsfromaroundtheworldstudythegeneticandenvironmental
factorsinfluencingthedevelopmentofthedisease,however,andsofar,thisareaof
medicalgeneticsisfullofconflictingresultsobtainedbydifferentresearchersfrom
differentcountries.
Wehaveproposedacross-isolatedpopulationapproach,implementedinethni-
cally and demographically subdivided genetic isolates with the aggregation of
specific complexdiseases. Unique geneticisolateswith the aggregation of certain
complex diseases, including schizophrenia, were ascertained in our long-term
population-genetic studies of small indigenous ethnics of Dagestan (Northern
Caucasus, Russia). Such cross-isolate approach allows us to identify common for
all observed isolates and specific for every of them genomic regions containing
candidate genes for diseases and genomic structural variants (CNV and ROH)
linked with schizophrenia. The study of the same complex phenotype in diverse
geneticisolateswithdifferentancestorsandhighrateofendogamyandinbreeding
enables the determination of the entire spectrum of genes and structural genomic
variants involved in the pathogenesis of schizophrenia or any other complex
disease. Genetic homogeneity and ancestor effect in such isolates helps identify
thegenomicmechanismsofthediseaseetiopathogenesiswithsubstantialsavingsof
cost and time, compared with genetically and ethnically heterogeneous large
populations.
Authorskeepcherishedmemoryofprominentgeneticists,whosesupportofour
pioneeringgeneticstudiesamongindigenouspeoplesofDagestanhadafundamen-
talimportanceforthedevelopmentoftheworkspresented—Timofeev-Resovskii,
Dubinin, and Gindilis. We also express our sincere gratitude to the staff of our
researchgroupofhumangeneticadaptationattheNIVavilovInstituteofGeneral
Genetics of RAS (VIGG RAS), and members of the regular expeditions in
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x Preface
Dagestan— Pavlova, Gurgenova, Kurbanov, Guseynova, and Omarova. We are
gratefultoPolitov,Kurbatova,andalltheresearchersoftheDepartmentofPopu-
lationGeneticsofVIGGRASforreviewandrecommendationtopublishourlong-
term study results in this book. We are also grateful to the reviewer of the book
manuscript—to Professor Golimbet, whose valuable comments in the manuscript
helpedtoimprovethepresentationofourstudyinthisbook.
Endless gratitude to our foreign colleagues, whose appreciation and support of
our Dagestan Genetic Heritage research program was of fundamental importance
for the preservation and development of this study, in spite of the numerous
difficultiesintheRussianscience.TheyareoutstandingscientistsfromtheUnited
States—ErvingGottesman,PaulThompsonandtheInternationalScientificCorpo-
ration ENIGMA, Ming Tsuang, Hilary Coon, Henry Harpending, Lynn Jorde,
Michael Hammer, and Tatiana Karafet; from Italia—Giorgio Paoli and Sergio
Tofanelli; from Germany Klaus-Peter Lesch; and from Japan Toru Takumi and
HideshiKawakami.Ourinternshipsandjointworkintheirlaboratorieshelpedthe
authors of this book to master the most advanced methods of molecular genetics
andbioinformaticstechnologiesandapplytheminourstudiesinDagestangenetic
isolates.
Endlessthanks toourcoauthoringenetic studies ofschizophreniainDagestan
isolatesandscientificeditorofthebook—Prof.StephenGlatt.Hisparticipationin
thisstudyassistedinovercomingthedifferencesinclinicalandgeneticmethodol-
ogiesbetweenRussianandUSresearchesandcertainlymadeavailabletheresults
of our research in this book to a wide range of English-speaking colleagues and
readers.
EndlessthankstoallDagestanhighlandersfromdiverseethnicgroupsfortheir
volunteerparticipationinourlong-termstudy.
Theauthorsaregratefulforthehelpinpreparingthemanuscriptforpublication
toGurgenovaandforEnglishtranslationstoMarisaPeryer.
Moscow,Russia KazimaBulayeva
Moscow,Russia OlegBulayev
Syracuse,NY,USA StephenGlatt
[email protected]
Contents
1 CurrentProblemsofComplexDiseaseGenesMapping. . . . . . . . . . 1
1.1 GeneralProblemsofComplexDiseaseGenesMapping. . . . . . . . 1
1.2 CurrentApproachesofSchizophreniaSpectrumDiseaseGene
Mapping. . . .. . . . . . . . . .. . . . . . . . . .. . . . . . . . . .. . . . . . . . . 2
1.3 TheCurrentStateofGeneMappingofSchizophreniaSpectrum
Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2 DescriptionsandMethodsofStudyinSelectedGeneticIsolatesof
Dagestan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2.1 HistoryandEthno-linguisticDiversityofDagestan. . . . . . . . . . . . 21
2.2 GeneticandDemographicStructureoftheSelectedIsolates. . . . . 22
2.3 MethodsofClinicalStudies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.4 Molecular-GeneticMethodsofStudy. . . . . . . . . . . . . . . . . . . . . . 30
2.5 GeneticandStatisticalMethodsofExperimental
DataAnalysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
3 SelectionofPopulationsforMappingGenesofComplexDiseases. . . 37
3.1 PrinciplesofSelectionofPopulationsforComplexDiseaseGene
Mapping. . . .. . . . . . . . . .. . . . . . . . . .. . . . . . . . . .. . . . . . . . . 37
3.2 EthnogenomicStructureofDagestanPopulations. . . . . . . . . . . . . 38
3.3 GeneticEpidemiologyStudyofSelectedGeneticIsolateswiththe
AggregationofSchizophreniaSpectrumDisorders. . . . . . . . . . . . 48
3.4 GenePoolofSelectedIsolatesforMappingGenesof
Schizophrenia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
3.5 RoleofInbreedingintheAggregationofaSchizophrenia
andinItsAgeofOnset. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
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