Relationship Of Candidate Genes And Alleles To Behavior

候选等位基因和基因假设从药理学和遗传学的发现进行了测试。此外，我们跟进全基因组连锁的发现。候选基因连锁调查包括：DRD2 Ser311Cys/酒精中毒，HTR1B/反社会酒精中毒，SLCA4/焦虑，COMT/精神分裂症/焦虑/烦躁/执行认知。表型，采样框架，遗传结构[例如TDT，兄弟姐妹]和功率进行评估。评估通常采用结构化访谈，通常采用中间表型和/或额外的末端表型。芬兰的数据集是从犯罪酒精先证者中确定的，因此丰富了II型[早发性]酒精中毒。西南印第安人、平原印第安人、十部落和芬兰的数据集来自分离株；精神病学访谈对照可从源人群中获得。正在使用中国和德国的病例/对照数据集。主要是非裔美国人可卡因数据集[N=800]正在使用中。剩下的数据集几乎都是白种人。大约有980名接受过精神病学采访的高加索人口控制人员。SW Indian数据集包含600对兄弟姐妹，SLCA4研究中使用的芬兰数据集包含366对兄弟姐妹，Plains Indian EEG数据集包含大量的兄弟姐妹和相对对。一项疼痛阈值研究[Dionne， Iadarola]被设计为兄弟姐妹-父母四方，实现定量的兄弟姐妹联系和TDT。两个精神分裂症数据集[Egan & Weinberger， Malhotra]都支持TDT/sTDT分析。病例/对照的关联能力取决于等位基因频率、关联强度和期望的α水平。我们测试的功能等位基因具有中等频率[HTR2C， HTR2A， mu阿片受体：0.1]或高频率[SLCA4和COMT: 0.4]，已知影响酒精中毒的ADH2 Arg47His和ALDH2 Glu487Lys的功能多态性具有5-10倍的作用。因此，我们最小的数据集[n=50]在p小于0.01的水平上有58%的功效；对于酒精中毒[几个数据集]、精神分裂症、强迫症、神经性厌食症、SAD和双相情感障碍的大型数据集，功率基本上是100%。对于较低的效应量，在较大的数据集中，当关联强度为0.1时，p < 0.01的功率仍然很高[大于0.8]。候选基因和等位基因与行为的关系：DRD2。DRD2多巴胺受体，“奖励缺失基因”假说，在西南印第安人中用三个DRD2标记进行了测试：先前涉及的Taq1A标记，STR和Ser311Cys， Ser311Cys损害信号转导，与高加索人[0.03]相比，该特定人群中的Ser311Cys要丰富得多[0.16]。由于Cys311损害功能，因此它是未知DRD2等位基因的替代品，这些等位基因以相似的程度或通过相同的机制[转导]减弱功能。尽管数据集包含15个Cys311/Cys311纯合子，但没有兄弟姐妹连锁或关联。此前，LNG报告了在种族匹配、精神病学访谈的酗酒者和对照组、严重酗酒者和父母酗酒的酗酒者中，DRD2和酒精中毒的早期阴性结果。LNG还发现了DRD2等位基因和单倍型频率的巨大种族差异，并参与了Ser311Cys的发现。随后，COGA兄弟姐妹连锁研究[Edenburg等]也未能检测到DRD2连锁信号。这些结果表明，很少有证据表明DRD2变异在酒精易感性中起重要作用。为了监测DRD2位点的功能变异，LNG开发了Ser311Cys和-141DelT的高通量检测方法。在对10个位点的DRD2单倍型的研究中，我们在两个大型数据集中发现了与阿片类药物依赖的正相关。行为的候选等位基因：血清素转运体。功能性血清素转运蛋白启动子多态性与维度测量的焦虑相关。在366对芬兰兄弟姐妹中进行的定量联系将这种多态性与TPQ的两个与焦虑相关的子量表联系起来[Mazzanti]。通过体内转运体密度的B-CIT SPECT成像进一步研究功能。在对照组中（不包括酗酒者），较低的转录s等位基因与较低的脑转运体密度有关。酗酒者会经历血清素转运功能的持续变化，例如由于酒精诱导的血清素释放或戒断的影响。这种多态性与认知恐惧挑战引起的杏仁核代谢活动有关。我们以小鼠遗传模型的发现为基础，确定5HT1B受体在酒精中毒亚型中的潜在作用。通过定位小鼠酒精偏好QTL和随后发现HTR1B敲除小鼠表现出增加的攻击性和对酒精的偏好，HTR1B被认为是一个潜在的酒精偏好基因。作为一种终端自身受体，5HT1B调节5 -羟色胺的释放，是酒精偏好和攻击性变化的极好候选者，独立于小鼠的研究结果。攻击性和冲动行为在两种精神病诊断中都有体现——反社会人格障碍和间歇性爆炸障碍，酒精偏好是酒精中毒的一个组成部分。对于HTR1B，我们使用了G861C[由我们描述]和密切相关的D6S284 STR。我们研究了640名芬兰受试者，包括350对兄弟姐妹[220对未受影响，79对不一致，51对受影响]和418名西南印第安人，包括305对兄弟姐妹[223对未受影响，71对不一致，11对受影响]，并根据存在/不存在反社会酒精中毒[DSMIII-R酒精中毒加上ASPD或IED]进行分类。在这项单位点研究中，在两个数据集中都发现了ibd关联的证据[p=0.04和p=0.01]，并且在芬兰人中也检测到与HTR1B的关联。候选基因和等位基因与行为的关系：COMT（儿茶酚- o -甲基转移酶）。COMT Val158Met与额叶功能：中等表型。位于额叶的执行认知功能（ECF）被认为在一些精神疾病中受损：酗酒、多动症和精神分裂症(z)。患有SZ的患者，以及在较小程度上他们的健康兄弟姐妹，在这些任务中有工作记忆和ecf的缺陷，并且在fMRI上显示出过度的皮层活动[因此被认为是低效的]。因此，有人提出额叶执行功能是一种重要的中间表型。我们发现功能性COMT变体与额叶认知功能存在基因剂量关系。在几个人群中可以看到这种关系：SZ、中重度头部损伤和对照组，他们的基线功能有很大差异。多巴胺在额叶任务中提高前额皮质的效率。Val158Met是一种常见的COMT变体，导致酶活性降低四倍，因此是额叶认知功能变异的优秀候选基因。此外，三个TDT连锁研究发现了SZ中存在Val158Met的证据，并且在22q11附近发现了SZ位点的一些证据。在75名对照、184名SZ和222名SZ的兄弟姐妹中，对比COMT基因型评估了Wisconsin Card Sort的表现，结果发现SZ患者和对照组都存在显著的等位基因剂量关系。这一发现在正常对照和头部受伤患者中得到了重复，然后在N-back任务中使用血氧水平依赖[BOLD]功能磁共振成像（fMRI）对个体额叶代谢活动的研究中得到了扩展，该任务访问前额叶认知功能。Val158等位基因与额叶代谢活性增加有关，这与皮层效率降低的假设相一致。Val等位基因可能有相反的优势：在两个人群中，Met等位基因预示着女性的焦虑和额叶脑电图一致性的降低。

Candidate allele & gene hypotheses developed from pharmacological & genetic findings are tested.. Also, we follow up on whole genome linkage findings. Candidate gene linkage investigations included: DRD2 Ser311Cys/alcoholism, HTR1B/antisocial alcoholism, SLCA4/anxiety, & COMT/Schizophrenia/anxiety/dysphoria/Executive cognition. Phenotype, sampling framework, genetic structures [e.g. TDT, sibpairs], & power are evaluated. Assessment is generally with structured interview, & usually with intermediate phenotypes and/or additional end-phenotypes. The Finnish dataset was ascertained from criminal alcoholic probands & is thus enriched for Type II [early onset] alcoholism. SW Indian, Plains Indian, Ten Tribes, & Finnish datasets are derived from isolates; psychiatric interviewed controls are available from source populations. Chinese and German case/control datasets are in use. Apredominantly African American cocaine dataset [N=800] is in use. Remaining datasets are almost entirely Caucasian. Some 980 psychiatrically interviewed Caucasian population controls are available. The SW Indian dataset includes 600 sibpairs, the Finnish dataset used in the SLCA4 study included 366 sibpairs, & the Plains Indian EEG dataset contains a large number of sib & relative pairs. A pain threshold study [Dionne, Iadarola] is designed as sib-parent quad enabling quantitative sibpair linkage & TDT. Both schizophrenia datasets [Egan & Weinberger, Malhotra] enable TDT/sTDT analysis. Power for case/control association is dependent on allele frequency, association strength, & desired level of alpha. The functional alleles we test have moderate [HTR2C, HTR2A, mu opioid receptor: 0.1] or high [SLCA4 & COMT: 0.4] frequencies, & the functional polymorphisms known to affect alcoholism ADH2 Arg47His & ALDH2 Glu487Lys have 5-10 fold effects. Therefore, our smallest datasets [n=50] have 58% power at the p less than 0.01 level; power is essentially 100% for larger datasets available for alcoholism [several datasets], schizophrenia, OCD, anorexia nervosa, SAD, & bipolar. For lower effect size, power at p less than 0.01 remains high [greater than 0.8] for the association strength of 0.1 in the larger datasets. Relationship of candidate genes and alleles to behavior: DRD2. The DRD2 dopamine receptor, "Reward Deficiency Gene" hypothesis, was tested in SW Indians with three DRD2 markers: the Taq1A marker previously implicated, an STR, & Ser311Cys, which impairs signal transduction & which is far more abundant [0.16] in this particular population as compared to Caucasians [0.03]. Because it impairs function, Cys311 is a surrogate for unknown DRD2 alleles that attenuate function to a similar extent or by the same mechanism [transduction]. There was no sibpair linkage nor association, although the dataset included 15 Cys311/Cys311 homozygotes. Previously, LNG reported the early negative results for DRD2 & alcoholism in ethnically matched, psychiatrically interviewed alcoholics & controls, in severe alcoholics, & in alcoholics with parental alcoholism. LNG also identified large ethnic differences in DRD2 allele & haplotype frequencies, & participated in the discovery of Ser311Cys. Subsequently, the COGA sibpair linkage study [Edenburg et al] has also failed to detect a DRD2 linkage signal. These results suggest there is scant evidence for a substantial role for DRD2 variation in alcohol vulnerability. To monitor functional variants at DRD2 locus, LNG has developed high throughput assays for Ser311Cys & -141DelT. In work with a ten-locis DRD2 haplotype, we find positive linkage to opioid dependence in two large datasets. Candidate alleles to behavior: Serotonin transporter. A functional serotonin transporter promoter polymorphism was associated with dimensionally measured anxiety. Quantitative linkage in 366 Finnish sibpairs linked this polymorphism to the two anxiety-related subscales of the TPQ [Mazzanti]. Functionality was further pursued by in vivo B-CIT SPECT imaging of transporter density. In controls [but not alcoholics], the lower transcribing s allele was associated with lower brain transporter density. Alcoholics experience sustained changes in serotonin transporter function, for example due to alcohol-induced serotonin release or effects of withdrawal. The polymorphism was linked to metabolic activity in amygdala induced by a cognitive fear challenge. We built on findings from mouse genetic models to identify a potential role for the 5HT1B receptor in a subtype of alcoholism. HTR1B was implicated as a potential alcohol preference gene by location of a mouse alcohol preference QTL & subsequent discovery that the HTR1B knockout mouse exhibited increased aggression & preference for alcohol. As a terminal autoreceptor, 5HT1B modulates serotonin release & was an excellent candidate for variation in alcohol preference & aggressivity, independently of the mouse findings. Aggressive & impulsive behaviors are represented in two psychiatric diagnoses - ASPD & IED [Intermittent Explosive Disorder] & alcohol preference is a component of alcoholism. For HTR1B, we used G861C [described by us] & the closely linked D6S284 STR. We studied 640 Finnish subjects included 350 sibpairs [220 unaffected, 79 discordant & 51 affected] & 418 Southwestern Indians including 305 sibpairs [223 unaffected, 71 discordant & 11 affected pairs] & classified for the presence/absence of antisocial alcoholism [DSMIII-R alcoholism plus either ASPD or IED]. In this single-locus study, evidence for i.b.d. linkage was found in both datasets [p=0.04 & p=0.01] & association to HTR1B was also detected in Finns. Relationship of candidate genes and alleles to behavior: COMT (catechol-O-methyltransferase). COMT Val158Met & Frontal lobe function: Intermediate phenotype. Executive cognitive functions (ECF)localized to the frontal lobe are thought to be impaired in several psychiatric diseases: alcoholism, ADHD, & schizophrenia SZ). Patients with SZ, & to a lesser extent their healthy siblings, have deficits in working memory & ECFs & show excess cortical activity with fMRI [& are thus said to be inefficient] during these tasks. It has therefore been proposed that frontal lobe executive functions represent an important intermediate phenotype. We found a gene-dosage relationship of a functional COMT variant to frontal cognitive function. The relationship was seen across several populations: SZ, moderate-severe head injury, & controls, which differ substantially in baseline function. Dopamine enhances prefrontal cortical efficiency during frontal lobe tasks. Val158Met, a common COMT variant, leads to four-fold reduction in enzyme activity & was thus an excellent candidate gene for variation in frontal lobe cognitive function. Also, three TDT linkage studies had detected evidence for Val158Met in SZ & some evidence for a SZ locus had been found near 22q11. Wisconsin Card Sort performance was evaluated versus COMT genotype in 75 controls, 184 SZs, & 222 siblings of SZs, with the result that a remarkable allele-dosage relationship was found to preserve errors in both the SZ patients & the controls. This finding was replicated in normal controls and head-injured patients, and then expanded by a study of frontal lobe metabolic activity in individuals evaluated using blood oxygen level dependent [BOLD] fMRI during the N-back task, which accesses prefrontal cognitive functions. The Val158 allele was associated with increased metabolic activity in frontal lobe consistent with the hypothesis of diminished cortical efficiency. The Val allelee may have counteradvantages: in a two populations the Met allele predicted anxiety in women and decreased frontal EEG coherence.