Statistical methods to localize disease heritability and identify biological mechanisms

定位疾病遗传性并确定生物学机制的统计方法

• 批准号: 10431843
• 负责人: Benjamin Michael Neale
• 金额: $ 84.67万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2023-08-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431843
• 关键词: Area; Attention deficit hyperactivity disorder; Binding; Biological; Biological Process; Bipolar Disorder; Chromatin; Collaborations; Communities; Complex; Computer software; Data; Data Set; Disease; Ensure; Frequencies; Gene Expression Regulation; Genes; Genetic; Genetic Variation; Genetic study; Genotype; Growth; Haplotypes; Heritability; Human Genome; Individual; Learning; Localized Disease; Major Depressive Disorder; Mental disorders; Methods; Population; Positioning Attribute; Psychopathology; Publications; Research; Risk; Sampling; Schizophrenia; Statistical Methods; Technology; Tissues; Trans-Omics for Precision Medicine; Variant; Work; autism spectrum disorder; base; biobank; disorder risk; epigenomics; exome sequencing; genetic variant; genome sequencing; genome wide association study; genome-wide; human disease; insight; next generation; novel; open source; open source tool; programs; psychiatric genomics; rare variant; statistics; trait; transcription factor; whole genome

ABSTRACT Genetic studies of both common and rare genetic variation have been extremely successful in identifying genes and variants associated to schizophrenia, autism and other psychiatric disorders. Nevertheless, for most psychiatric disorders, the vast majority of genetic effects are as yet undetected. Our specific aims are to 1) quantify the heritability explained by rare and functional classes of variation; 2) boost association power via leveraging related traits; and 3) infer biological mechanisms via local fine-mapping and genome- wide causal inference. We will guide our research using >800,000 samples from genome-wide association, exome sequencing and genome sequencing studies of psychiatric disease. The methods we propose to develop will be implemented in software packages that we will make widely available to the community.

摘要 对常见和罕见遗传变异的遗传学研究在识别 与精神分裂症、自闭症和其他精神疾病相关的基因和变异。但在 大多数精神疾病，绝大多数遗传效应尚未被发现。我们的具体目标是 1）量化由罕见和功能性变异类别解释的遗传力; 2）增强关联 通过利用相关性状的力量;和3）通过局部精细映射和基因组推断生物机制- 广泛的因果推理。我们将使用来自全基因组关联的> 80万个样本来指导我们的研究， 外显子组测序和基因组测序的研究。我们提出的方法 develop将以软件包的形式实现，我们将广泛提供给社会。

项目成果

Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types.

• DOI: 10.1038/s41588-018-0081-4
• 发表时间: 2018-04
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Finucane HK;Reshef YA;Anttila V;Slowikowski K;Gusev A;Byrnes A;Gazal S;Loh PR;Lareau C;Shoresh N;Genovese G;Saunders A;Macosko E;Pollack S;Brainstorm Consortium;Perry JRB;Buenrostro JD;Bernstein BE;Raychaudhuri S;McCarroll S;Neale BM;Price AL
• 通讯作者: Price AL

LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis.

• DOI: 10.1093/bioinformatics/btw613
• 发表时间: 2017-01-15
• 期刊: Bioinformatics (Oxford, England)
• 作者: Zheng J;Erzurumluoglu AM;Elsworth BL;Kemp JP;Howe L;Haycock PC;Hemani G;Tansey K;Laurin C;Early Genetics and Lifecourse Epidemiology (EAGLE) Eczema Consortium;Pourcain BS;Warrington NM;Finucane HK;Price AL;Bulik-Sullivan BK;Anttila V;Paternoster L;Gaunt TR;Evans DM;Neale BM
• 通讯作者: Neale BM

Functional equivalence of genome sequencing analysis pipelines enables harmonized variant calling across human genetics projects.

• DOI: 10.1038/s41467-018-06159-4
• 发表时间: 2018-10-02
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Regier AA;Farjoun Y;Larson DE;Krasheninina O;Kang HM;Howrigan DP;Chen BJ;Kher M;Banks E;Ames DC;English AC;Li H;Xing J;Zhang Y;Matise T;Abecasis GR;Salerno W;Zody MC;Neale BM;Hall IM
• 通讯作者: Hall IM

Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk.

• DOI: 10.1038/s41588-018-0196-7
• 发表时间: 2018-10
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Reshef YA;Finucane HK;Kelley DR;Gusev A;Kotliar D;Ulirsch JC;Hormozdiari F;Nasser J;O'Connor L;van de Geijn B;Loh PR;Grossman SR;Bhatia G;Gazal S;Palamara PF;Pinello L;Patterson N;Adams RP;Price AL
• 通讯作者: Price AL

A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder.

• DOI: 10.1016/j.biopsych.2017.11.026
• 发表时间: 2018-06-15
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Martin J;Walters RK;Demontis D;Mattheisen M;Lee SH;Robinson E;Brikell I;Ghirardi L;Larsson H;Lichtenstein P;Eriksson N;23andMe Research Team;Psychiatric Genomics Consortium: ADHD Subgroup;iPSYCH–Broad ADHD Workgroup;Werge T;Mortensen PB;Pedersen MG;Mors O;Nordentoft M;Hougaard DM;Bybjerg-Grauholm J;Wray NR;Franke B;Faraone SV;O'Donovan MC;Thapar A;Børglum AD;Neale BM
• 通讯作者: Neale BM