复旦医学遗传学课件06疾病的多基因遗传

06疾病的多基因遗传PolygenicInheritance疾病的多基因遗传前言数量性状的多基因遗传多基因病的遗传前言微效基因（minorgene）人类的一些遗传性状或某些遗传病的遗传基础不是一对主基因，而是几对基因，每一对基因对遗传性状或遗传病形成的作用是微小的。多基因遗传（polygenicinheritance）性状或疾病的遗传方式取决于两个以上微效基因的累加作用，还受环境因子的影响，因此这类性状也称为复杂性状或复杂疾病（complexdisease）。Themultifactorialmodelis(1)Several,butnotanunlimitednumber,lociareinvolvedintheexpressionofthetrait.(2)Thereisnodominanceorrecessivityateachoftheseloci.(3)Thelociactinconcertinanadditivefashion,eachaddingordetractingasmallamountfromthephenotype.(4)Theenvironmentinteractswiththegenotypetoproducethefinalphenotype.多基因遗传受环境因子的影响常见的多基因疾病近视高血压糖尿病精神分裂症哮喘数量性状的多基因遗传质量性状（qualitativecharacter）数量性状（quantitativecharacter）数量性状的遗传规规律数量性状的遗传规律多基因病的遗传易患性（liability）在多基因遗传病发生中，遗传因素和环境因素共同作用决定一个个体患某种遗传病的可能性称为易患性。易感性（susceptibility）易感性特指由遗传因素决定的患病风险，仅代表个体所含有的遗传因素；但在一定的环境条件下，易感性高低可代表易患性高低。发病阈值（threshold）当一个个体易患性高到一定限度就可能发病。这种由易患性所导致的多基因遗传病发病最低限度称为发病阈值。群体易患性变异分布图正态分布曲线中与关系易患性的平均值和阈值距离与患病率关系遗传度及其估算遗传度（heritability）多基因累加效应对疾病易患性变异的贡献大小。遗传度愈大，表明遗传因素对病因的贡献愈大。疾病遗传度精神分裂症80%哮喘80%唇裂±腭裂76%唇裂遗传度76%精神分裂症遗传度80%遗传度的估算Falconer公式rbh2grgaXXbcrccaXXpb)(Xg－一般群体易患性平均值与阈值之间的标准差数Xc－对照组亲属中的易患性平均值与阈值之间的标准差数Xr－先证者亲属易患性平均值与阈值之间的标准差数ag－一般群体易患性平均值与一般群体中患者易患性平均值之间的标准差数r－－亲属系数ar－先证者亲属易患性平均值与先证者亲属中患者易患性平均值之间的标准差数qg－一般群体发病率qc－对照亲属发病率，Pc－1-qcqr－先证者亲属发病率例题1先天性房间隔缺损在一般群体中的患病率为0.1％，在100个先证者的家系中调查，先证者的一级亲属共有669人(双亲200人，同胞279人，子女190人)，其中有22人发病。先证者一级亲属的患病率22／669×100％＝3.3％查Falconer表，按群体患病率查得Xg和ag，再根据亲属患病率查得Xr，然后代入公式求出b值。q%=0.1X=3.090a=3.367q%=3.3%X=1.838b=(3.090-1.838)/3.367=0.37r=0.5＝0.37/0.5=74%rbh2例题2江苏启东调查结果：肝癌一级亲属6591人，359人发病，q=5.45%，对照组5227名一级亲属，54人发病，q=1.03%。q=5.45%，X=1.603q=1.03%，X=2.315a=2.655P=1-q=1－0.0103=0.987b=0.2654h2=b/r=0.2654/0.5=0.53=53%crccaXXpb)(Holzinger公式Holzinger公式CMZ－一卵双生子的同病率CDZ－二卵双生子的同病率DZDZMZCCCh1002＝例题对躁狂抑郁性精神病的调查表明，在15对单卵双生子中，共同患病的有10对；在40对双卵双生子中，共同患病的有2对。依此来计算单卵双生子的同病率为67％，双卵双生子的同病率为5％。代入上式：%6565.051005671002DZDZMZCCCh影响多基因遗传病再发风险估计的因素患病率与亲属级别有关例如：无脑畸形和脊柱裂的患病率为0.38％，在图中横轴上查出0.38之点，作一垂直线与纵轴平，已知此病的遗传度为60％，从图中找出遗传度60％的斜线，把它和0.38的垂直线相交点作一横线在纵轴上的一点近于4，即表明该病的一级亲属患病率接近4％。影响多基因遗传病再发风险估计的因素患者亲属再发风险与亲属中受累人数有关患者亲属再发风险与患者畸形或疾病严重程度关影响多基因遗传病再发风险估计的因素多基因遗传病的群体患病率存在性别差异时，亲属再发风险与性别有关群体患病率较低即阈值较高的那种性别罹患，则患者亲属的发病风险较高。例如人群中男性先天性幽门狭窄的患病率高于女性，男性患病率为0.5％，女性患病率为0.1％，男性的患病率比女性高5倍，即男性发病阈值低于女性。男性患者的儿子患病率是5.5％，女儿的患病率2.4％。如为女性患者，其儿子的患病率达到19.4％，女儿的患病率达到7.3％。表明女性患者比男性患者带有更多的致病基因。(1)Recurrenceriskincreaseswiththenumberofaffectedchildreninafamily.(2)Recurrenceriskincreaseswithseverityofthedefect.Amoreseverelyaffectedparentismorelikelytoproduceanaffectedchild.(3)Consanguinityslightlyincreasestheriskforanaffectedchild.(4)Ifthetwosexeshaveadifferentprobabilityofbeingaffected,theleastlikelysex,ifaffected,isthemostlikelysextoproduceanaffectedoffspring.Risk1.schizophrenia,SPSchizophreniaisahumorousbraindisordercharacterizedbydelusionalthinkinganduniquebutunpopularperceptions.Schizophreniaaffects1%oftheworldpopulation.Netherlandishpainter:vangoghGermanmusician:RobertAlexanderSchumannRelationshipRiskMonozygotictwins40-50%Dizygotictwins17%Children13%Siblings10%Halfsiblings6%Grandchildren5%Nieces,Nephews4%Aunts,Uncles,Cousins2%GeneralPopulation1%Mentalhealthprofessionalsnormallydiagnosethisillnessif,duringanyone-monthperiodofaperson’slife,thatpersonhassufferedtwoormoreofthefollowing:DelusionsHallucinationsDisorganizedspeechGrosslydisorganizedorcatatonicbehaviorNegativesymptomsNegativesymptomsarethemostinsidiousbehavioraleffectsofschizophrenia.Theycanincludelowlevelsof:InterestMotivationEmotionalarousalMentalactivitySocialdriveSpeechSchizophreniaisequallyrepresentedinwomenandmen.Theonsetoftheillnessgenerallyoccursatalaterageinwomenthaninmen(betweenages23and35inwomenversus18to25formen).Notonlydowomengenerallypresentwithschizophreniaatlaterages,butthephenomenonoflateonsetschizophrenia(40+years)isalmostentirelyafemaleone.SubtypesofSchizophrenia1.DisorganizedType2.CatatonicType3.ParanoidType4.UndifferentiatedType5.ResidualType(waitingforpsychiatry)CausesofschizophreniaThecauseofschizophreniaisunknown.Manymentalhealthprofessionalsbelievetherearefactorswhichincreaseanindividual’sriskofhavingschizophrenia.Forexample,first-degreebiologicalrelativesofpersonswithschizophreniahaveatentimesgreaterriskofdevelopingtheillnessthanmembersofthegeneralpopulation.Becausethereisnocureforschizophrenia,thegoaloftreatmentistoeliminateorreducesymptoms,minimizesideeffects,preventrelapse,andsociallyandoccupationallyrehabilitatethepatient.mentalhealthprofessionalsgenerallybeginadvisingtheirpatientsoftheschizophreniclikelihoodofsuicide.Relatedgenes——DRDgenesDRD3genedopaminereceptorD3,locatedon3q13.3normalfunctionoftheDRD3geneTheDRD3geneprovidesinstructionsformakingaproteincalleddopaminereceptorD3,whichisfoundinthebrain.Thisproteinrespondstothechemicalmessenger(neurotransmitter)dopaminetotriggersignalswithinthenervoussystem,includingsignalsinvolvedinproducingphysicalmovement.excitatoryneurotransmitterDRD3expressedinendbrain、hippocampi（EmotionalarousalMentalactivity）antagonistofDRD3receptorDRD2gene(11q22.1-11.3)141cmissingDRD4gene(11