Integrative genetics of behavior with high throughput technologies

行为的综合遗传学与高通量技术

• 批准号: 7732115
• 负责人: David Goldman
• 金额: $ 234.88万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7732115
• 关键词: 4-aminospiroperidol; Adult; African American; Alcohol dependence; Alcoholism; Alleles; American Indians; Anorexia Nervosa; Anti-Anxiety Agents; Antipsychotic Agents; Anxiety; Anxiety Disorders; Asperger Syndrome; Behavior; Behavioral; Behavioral Genetics; Brain; Brain imaging; Brain-Derived Neurotrophic Factor; COMT gene; Candidate Disease Gene; Catechol O-Methyltransferase; Child; Childhood; Clinical; Clozapine; Cocaine; Cognition; Cognitive; Cognitive deficits; Colorado; Complex; Control Locus; Craniocerebral Trauma; DRD2 gene; Data Set; Databases; Dependence; Depressed mood; Detection; Diagnosis; Diazepam; Disease; Dopamine; Electroencephalography; Emotional; Environmental Risk Factor; Episodic memory; Equilibrium; Ethanol Metabolism; Exposure to; Extramural Activities; Family; Frequencies; Functional Magnetic Resonance Imaging; GTP Cyclohydrolase; Gene Cluster; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Genetic Structures; Genetic Transcription; Genetic Variation; Genome; Genome Scan; Genotype; HTR2A gene; Haplotypes; Histones; Individual; Interview; Link; Linkage Disequilibrium; Macaca mulatta; Maternal Deprivation; Measures; Mediating; Medical; Mental disorders; Methaqualone; Methylation; Minisatellite Repeats; Naltrexone; Nature; Neurobiology; Neuropeptides; Opiate Addiction; Other Finding; Outcome; Pain; Pain Threshold; Pathology; Patients; Phenotype; Play; Population; Positron-Emission Tomography; Promoter Regions; Proteins; Rate; Reporting; Research Personnel; Resistance; Risk; Risk Factors; Role; Sampling; Sampling Studies; Scanning; Schizophrenia; Score; Selective Serotonin Reuptake Inhibitor; Serotonin; Signal Transduction; Single Nucleotide Polymorphism; Source; Stratification; Stress; Structure; Substance Addiction; Suicide; Universities; Variant; Virginia; Washington; Woman; addiction; alcohol response; anti social; base; carfentanil; chronic pain; cognitive function; college; dosage; early onset; follow-up; functional genomics; gain of function; gene interaction; genetic analysis; genetic linkage analysis; genome wide association study; high throughput technology; monoamine; neurogenetics; neuropeptide Y; next generation; novel; proband; problem drinker; promoter; response; serotonin transporter; size; trait

Identification of functional variants is part of the end-game of genetic analysis or perhaps the real starting point to understand roles of genes in behaviors. Public databases are populated with >12 million sequence variants, mostly single nucleotide polymorphisms. However, most rare and uncommon (<0.05) variants are unknown, and functionality of most is unknown. We discovered polymorphisms in >50 neurogenetic candidate genes. Several alter function of the encoded protein, or gene expression. A rare, gain-of-function serotonin transporter variant Ile425Val leads to severe pathology including Asperger's syndrome, treatment resistant OCD, and anorexia nervosa, in two families in which it is segregating. In the promoter region of this gene the HTTLPR polymorphism alters transcription. At HTTLPR we described a common, functional allele (LA->LG), enabling us to detect linkage of the gain-of-function LA allele to OCD in two populations (Hu et al). Discovery of the new functional allele (LG) enhanced linkage studies of HTTLPR to behavioral phenotypes and intermediate phenotypes, as described later. The findings include linkage to SSRI treatment response of depressed patients, via the mechanism of treatment tolerability (Hu et al, 2007). Common HTR2C Ser23Cys and HTR2A Asn452His alleles were detected, shown to be functional (Lappalainen et al, Ozaki et al, Okada et al) and linked by others to clozapine responsive of schizophrenics. In first-episode schizophrenics, we helped show that a functional DRD2 promoter polymorphism influences antipsychotic response (Lencz et al, 2006). We first detected the OPRM1 Asn40Asp missense variant (Bergen et al). It was shown by others to be functional and linked by others, and recently by us (Anton et al, 2008), to naltrexone treatment response in alcoholics. Recently we traced linkages of NPY (Zhu et al, 2008), GCH1 (Tegeder et al) and DISC1 (Hodgkinson et al) to behavior to functional haplotypes and alleles. The association we demonstrated between a low expression Neuropeptide Y (NPY) haplotype and increased anxiety and emotionality is illustrative of the effect of functional genetic variation on multiple levels of brain function and on complex behavior. Genetically determined reduction of expression of this anxiolytic neuropeptide predicted reduced trait anxiety and liability to anxiety disorders and increased brain responses to emotional stiuli as shown by fMRI and to pain/stress as shown by C11-carfentanil PET (Zhou et al, Nature, 2008). We created a 1536 SNP Addictions Array enabling haplotype-based and candidate locus coverage of 130 genes, including genes in the domains of alcohol metabolism, stress/anxiety, monoamine function, and signaling. The array includes 186 ancestry informative markers (AIMs) selected on the basis that they differed 0.7 and 10-fold in frequency between at least two continental populations and balanced for continental populations. The AIMs were genotyped in 52 CEPH reference populations, representing >1000 individuals, enabling us to derive ancestry factor scores for each individual in our datasets. The factor scores are used as covariates, ruling out or correcting for effects of ethnic stratification. Use of the array by Extramural investigators was facilitated by our performing genotyping such that 25,000 individuals were genotyped from multiple study samples including Yale, Emory University, the Rockefeller University, Columbia University, University of Colorado, UCSD, Medical College of Virginia, Washington University, and NIDCR (Hodgkinson et al, 2008). We detected loci influencing alcoholism by whole genome linkage analysis and followed up several. At the Chr 4 GABAA subunit cluster implicated in a Plains Indian linkage scan (Long et al) linkage disequilibrium to the GABAA alpha 2 gene was found by others. We replicated the alpha 2 LD finding and showed that the association to dependence was anxiety-mediated, or modulated (Enoch et al). Another GABAA gene cluster implicated in alcoholism, and alcohol response, is located on Chr 5. Within this cluster we reported linkage disequilibrium to alcoholism (Radel et al) and implicated the GABAA alpha 6 gene, where we discovered a missense variant associated with alcohol dependence and response to alcohol and diazepam (Iwata et al, Schuckit et al). We completed a genome scan in Plains Indians yielding genome-wide significant, or near-significant, linkage to an alcoholism-associated EEG trait, as described (AA000280-18). Intermediate phenotypes augment diagnosis by structured interview. Clinical subphenotyping enabled linkage of HTR1B to antisocial alcoholism (Lappalainen et al), serotonin transporte r (SLCA4) to anxiety (Mazzanti et al; Hariri et al), BDNF Val66Met to episodic memory (Egan et al), COMT Val158Met to anxiety (Enoch et al), executive cognition (Egan et al; Lipsky et al; Malhotra et al), and pain threshold (Zubieta et al; Diatchenko et al), and GTP cyclohydrolase to chronic pain and experimental pain response (Tegeder et al). In these studies brain imaging and cognitive measures play prominent roles. Frontal cognitive deficit is a risk factor in schizophrenia, alcoholism and other diseases. Dopamine generally enhances prefrontal cortical efficiency. Met158, a common COMT variant, leads to four-fold reduction in COMT activity. It is thus a candidate allele for cognitive function via effect on frontal dopamine. We found an allele-dosage relationship of Met158 to frontal cognitive function and diminished frontal cortical efficiency (Egan et al). The relationship to cognition is observed in populations differing in baseline cognitive function: schizophrenia, moderate-severe head injury (Lipsky et al), & controls (Malhotra et al). LNG proposed that Val158 has a counter-advantage: stress resiliency. In two populations Met158 predicted anxiety in women and decreased frontal EEG coherence (Enoch et al), and Met158 was associated with lower resiliency to pain/stress (Zubieta et al; Diatchenko et al). Met158 predicted inability to activate endomorphin release after pain/stress (Zubieta et al).Overall, effect sizes of genes in intermediate phenotypes is >3 whereas the modal effect size of 24 common alleles in seven complex diseases found by whole genome association was approximately 1.9 (Goldman and Ducci, 2007). Sampling framework and genetic structures are exploited to enhance detection of GxE effects, to achieve greater homogeneity of genetic background and exposures, and to enrich for exposures and outcomes. A Finnish dataset was ascertained from criminal alcoholic probands & thus enriched for Type II early onset alcoholism. SW Indian, Plains Indian, & Finnish datasets are derived from isolates, with psychiatrically interviewed controls available from source populations. An African American cocaine/opioid dependence dataset N=1000 was powerful for detecting GxE of childhood adversity and HTTLPR in adult suicidality (Roy et al, 2007) because of high rates of adversity and suicidality in substance dependence. An MAOA functional VNTR previously linked to dyscontrol via stress interaction was linked to outcomes of alcohol dependence and ASPD in American Indian women, of whom approximately half had been sexually abused as children (Ducci et al, 2008). The genome-wide integrative approach has been amplified by large scale genotyping enabling whole genome association, and next generation sequencing. We completed an Illumina 550k genome-wide scan for EEG variation associated with alcoholism and other psychiatric diseases and discovered seven independent genome-wide significant loci controlling variation in the EEG. Next-generation sequencing was used to analyze brain histone methylation and transcriptome changes resulting from early maternal deprivation in Rhesus macaques.

功能变异的鉴定是基因分析的最后阶段，也可能是理解基因在行为中的作用的真正起点。公共数据库中有1,200万个序列变异，其中大部分是单核苷酸多态性。然而，大多数罕见和不常见（<0.05）的变异是未知的，大多数的功能是未知的。我们发现了bb50个神经遗传候选基因的多态性。有几种会改变编码蛋白的功能或基因表达。一种罕见的功能获得型血清素转运体变体Ile425Val在两个分离的家族中导致严重的病理，包括阿斯伯格综合症、治疗难治性强迫症和神经性厌食症。在该基因的启动子区域，HTTLPR多态性改变转录。在HTTLPR上，我们描述了一个常见的功能性等位基因（LA->LG），使我们能够在两个人群中检测到功能获得性LA等位基因与强迫症的联系（Hu等）。新的功能等位基因（LG）的发现加强了HTTLPR与行为表型和中间表型的连锁研究，如后面所述。研究结果包括通过治疗耐受性机制与抑郁症患者的SSRI治疗反应相关（Hu et al ., 2007）。检测到常见的HTR2C Ser23Cys和HTR2A Asn452His等位基因，显示出功能（Lappalainen等人，Ozaki等人，Okada等人），并与精神分裂症患者氯氮平反应有关。在首发精神分裂症患者中，我们帮助证明功能性DRD2启动子多态性影响抗精神病反应（Lencz et al, 2006）。我们首先检测到了OPRM1 Asn40Asp错义变体（Bergen等）。其他人和我们最近（Anton et al, 2008）都证明了它与纳曲酮治疗对酗酒者的影响有关。最近，我们追踪了NPY （Zhu et al ., 2008）、GCH1 （Tegeder et al .）和DISC1 （Hodgkinson et al .）与行为、功能单倍型和等位基因的联系。

项目成果

Serotonin transporter genotype and depressive phenotype determination by discriminant analysis of glucose metabolism under acute tryptophan depletion.

• DOI: 10.1016/j.neuroimage.2008.07.040
• 发表时间: 2008-12
• 期刊: NeuroImage
• 影响因子: 5.7
• 作者: Nugent AC;Neumeister A;Goldman D;Herscovitch P;Charney DS;Drevets WC
• 通讯作者: Drevets WC

Failure to detect DUP25 in lymphoblastoid cells derived from patients with panic disorder and control individuals representing European and American populations.

未能在来自恐慌症患者和代表欧洲和美国人群的对照个体的淋巴母细胞中检测到 DUP25。

• DOI: 10.1038/sj.ejhg.5201181
• 发表时间: 2004
• 期刊: European journal of human genetics : EJHG
• 作者: Zhu,Guanshan;Bartsch,Oliver;Skrypnyk,Cristina;Rotondo,Alessandro;Akhtar,LonginaA;Harris,Claudia;Virkkunen,Matti;Cassano,Giovanni;Goldman,David
• 通讯作者: Goldman,David

Deconstruction of vulnerability to complex diseases: enhanced effect sizes and power of intermediate phenotypes.

• DOI: 10.1100/tsw.2007.210
• 发表时间: 2007-11-02
• 期刊: TheScientificWorldJournal
• 作者: Goldman D;Ducci F
• 通讯作者: Ducci F

Impaired recognition of fear facial expressions in 5-HTTLPR S-polymorphism carriers following tryptophan depletion.

色氨酸耗尽后 5-HTTLPR S 多态性携带者对恐惧面部表情的识别能力受损。

• DOI: 10.1007/s00213-006-0581-2
• 发表时间: 2006
• 期刊: Psychopharmacology
• 影响因子: 3.4
• 作者: Marsh,AbigailA;Finger,ElizabethC;Buzas,Beata;Soliman,Niveen;Richell,RebeccaA;Vythilingham,Meena;Pine,DanielS;Goldman,David;Blair,RJR
• 通讯作者: Blair,RJR

Imaging genomics applied to anxiety, stress response, and resiliency.

成像基因组学应用于焦虑、压力反应和弹性。

• DOI: 10.1385/ni:4:1:51
• 发表时间: 2006
• 期刊: Neuroinformatics
• 影响因子: 3
• 作者: Xu,Ke;Ernst,Monique;Goldman,David
• 通讯作者: Goldman,David