Genome Wide Association Study of Bone Mineral Accretion During Childhood

儿童期骨矿物质沉积的全基因组关联研究

• 批准号: 8437217
• 负责人: Struan F A Grant
• 金额: $ 37.54万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8437217
• 关键词: 19 year old; 6 year old; Adolescence; Adolescent; Affect; African; African American; Age; Alleles; American; Behavioral; Biological; Biological Assay; Body Size; Bone Density; Bone Mineral Contents; Bone Resorption; Bone remodeling; Caucasians; Caucasoid Race; Child; Child Development; Child health care; Childhood; Cohort Studies; Collection; Copy Number Polymorphism; Data; Data Quality; Development; Diagnosis; Dietary Factors; Dietary intake; Disease; Enrollment; Ethnic Origin; Event; Failure; Forearm; Genes; Genetic; Genetic Determinism; Genotype; Goals; Growth; Growth and Development function; Haplotypes; Height; Hip region structure; Hispanics; Human; Institutes; International; Laboratories; Lead; Life; Life Cycle Stages; Linkage Disequilibrium; Longitudinal Studies; Maps; Measurement; Measures; Minerals; Modeling; Nature; Osteogenesis; Osteopenia; Osteoporosis; Osteoporosis prevention; Outcome; Pathway interactions; Pattern; Phase; Physical activity; Population; Population Control; Prevention; Procedures; Process; Puberty; Publishing; Reference Standards; Regulation; Relative (related person); Research Design; Risk; Risk Factors; Sampling; Signal Transduction; Skeleton; Staging; Stratification; Techniques; Testing; Time; Variant; Vertebral column; Visit; Woman; base; bone; bone health; bone loss; bone mass; cohort; critical period; density; design; genetic variant; genome wide association study; men; prepuberty; public health relevance; skeletal; trait; young adult

DESCRIPTION (provided by applicant): In 2002, over 43 million Americans over the age of 50 years had osteoporosis or osteopenia. That number is expected to increase to 61 million by 2020. Osteoporosis may have its origins during childhood growth and development, when the human skeleton undergoes rapid changes caused by the modeling and remodeling of bone. Bone mineral accretion occurs as consequence of bone formation occurring at a faster pace than resorption, resulting in both increasing size and greater mineral content of skeletal components. Failure to achieve optimal bone mineral accretion during the critical period of growth and development is likely to lead to suboptimal peak bone mass and osteoporosis later in life. Identifying the factors that influence bone mineral accretion during childhood has important implications for prevention of this common, disabling disorder. Most of what is known about childhood bone health is based on measures of bone mineral content (BMC) or density (BMD). A single BMC measurement reflects the lifetime of bone mineral acquisition to that point, and the cumulative outcome of all the factors that influenced bone acquisition. In contrast, bone mineral accretion, the change in BMC in a given time period reflects the recent factors influencing bone formation and resorption. Bone accretion occurs at a low rate prior to the adolescent growth spurt in height. During and after the adolescent growth spurt there is a sharp increase in bone accretion followed by a gradual decline. These distinct patterns of bone accretion suggest that bone accretion may be under different regulatory control at different phases of development. The goal of this study is to use genome wide association techniques to identify genetic variants associated with BMC status (BMC relative to age) and bone accretion, and determine if these genetic variants differ from childhood to young adulthood. The proposed study will take advantage of biological samples and data collected by the NICHD Bone Mineral Density in Childhood Study, a multi-center, longitudinal study of > 2,000 children and adolescents who have undergone annual BMD measurements for 3 to 7 years, along with assessment of growth, puberty status, dietary intake, physical activity and skeletal maturation. An additional 500 Caucasian children will be enrolled in the proposed study following identical procedures. A high-density tag-SNP array will be used to study genetic variants, including CNVs, that influence BMC and bone accretion. A discovery cohort of 945 Caucasian subjects will be analyzed and replication of the findings will be subsequently tested in the new Caucasian cohort (n=500) and further explored in the Hispanic subset (n=284). Signals that are successfully replicated will then be refined in the African-American (AA) sample (n=435), as the degree of linkage disequilibrium is lower in this group. Those variants identified in both AA and non-AA samples are likely to represent more universally important genes, and pathways for diagnosis, prevention, and treatment of bone acquisition abnormalities.

描述（由申请人提供）：2002 年，超过 4300 万 50 岁以上的美国人患有骨质疏松症或骨质减少。预计到 2020 年，这一数字将增加到 6100 万。骨质疏松症可能起源于儿童生长和发育期间，此时人体骨骼因骨骼的塑造和重塑而发生快速变化。骨矿物质积聚是骨形成速度快于骨吸收速度的结果，导致骨骼成分尺寸增大和矿物质含量增加。在生长和发育的关键时期未能实现最佳的骨矿物质积累可能会导致晚年骨量峰值不理想和骨质疏松症。确定儿童时期影响骨矿物质积累的因素对于预防这种常见的致残性疾病具有重要意义。关于儿童骨骼健康的大部分了解都是基于骨矿物质含量 (BMC) 或密度 (BMD) 的测量。单个 BMC 测量反映了到该点的骨矿物质获取的寿命，以及影响骨获取的所有因素的累积结果。相反，骨矿物质增加，即给定时间段内 BMC 的变化反映了影响骨形成和吸收的近期因素。在青少年身高突增之前，骨质增生的发生率较低。在青春期生长突增期间和之后，骨质增生急剧增加，然后逐渐下降。这些不同的骨增生模式表明，骨增生在不同的发育阶段可能受到不同的调控。本研究的目标是利用全基因组关联技术来识别与 BMC 状态（BMC 相对于年龄）和骨增生相关的遗传变异，并确定这些遗传变异在儿童期到成年早期是否存在差异。拟议的研究将利用 NICHD 儿童骨矿物质密度研究收集的生物样本和数据，这是一项多中心纵向研究，对超过 2,000 名儿童和青少年进行了 3 至 7 年的年度 BMD 测量和评估生长、青春期状态、饮食摄入、体力活动和骨骼成熟。另外 500 名白人儿童将按照相同的程序参加拟议的研究。高密度标签-SNP 阵列将用于研究影响 BMC 和骨增生的遗传变异，包括 CNV。将分析 945 名白人受试者的发现队列，随后将在新的白人队列 (n=500) 中测试研究结果的重复性，并在西班牙裔子集 (n=284) 中进一步探索。成功复制的信号将在非裔美国人 (AA) 样本 (n=435) 中进行细化，因为该组中连锁不平衡的程度较低。在 AA 和非 AA 样本中发现的这些变异可能代表更普遍重要的基因，以及诊断、预防和治疗骨获取异常的途径。

项目成果

Insights into the Genetic Underpinnings of Endocrine Traits from Large-Scale Genome-Wide Association Studies.

• DOI: 10.1016/j.ecl.2020.07.007
• 发表时间: 2020-12
• 期刊: Endocrinology and metabolism clinics of North America
• 影响因子: 4.5
• 作者: D. Cousminer;S. Grant

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

• DOI: 10.1371/journal.pgen.1008718
• 发表时间: 2020-10
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Vogelezang S;Bradfield JP;Ahluwalia TS;Curtin JA;Lakka TA;Grarup N;Scholz M;van der Most PJ;Monnereau C;Stergiakouli E;Heiskala A;Horikoshi M;Fedko IO;Vilor-Tejedor N;Cousminer DL;Standl M;Wang CA;Viikari J;Geller F;Íñiguez C;Pitkänen N;Chesi A;Bacelis J;Yengo L;Torrent M;Ntalla I;Helgeland Ø;Selzam S;Vonk JM;Zafarmand MH;Heude B;Farooqi IS;Alyass A;Beaumont RN;Have CT;Rzehak P;Bilbao JR;Schnurr TM;Barroso I;Bønnelykke K;Beilin LJ;Carstensen L;Charles MA;Chawes B;Clément K;Closa-Monasterolo R;Custovic A;Eriksson JG;Escribano J;Groen-Blokhuis M;Grote V;Gruszfeld D;Hakonarson H;Hansen T;Hattersley AT;Hollensted M;Hottenga JJ;Hyppönen E;Johansson S;Joro R;Kähönen M;Karhunen V;Kiess W;Knight BA;Koletzko B;Kühnapfel A;Landgraf K;Langhendries JP;Lehtimäki T;Leinonen JT;Li A;Lindi V;Lowry E;Bustamante M;Medina-Gomez C;Melbye M;Michaelsen KF;Morgen CS;Mori TA;Nielsen TRH;Niinikoski H;Oldehinkel AJ;Pahkala K;Panoutsopoulou K;Pedersen O;Pennell CE;Power C;Reijneveld SA;Rivadeneira F;Simpson A;Sly PD;Stokholm J;Teo KK;Thiering E;Timpson NJ;Uitterlinden AG;van Beijsterveldt CEM;van Schaik BDC;Vaudel M;Verduci E;Vinding RK;Vogel M;Zeggini E;Sebert S;Lind MV;Brown CD;Santa-Marina L;Reischl E;Frithioff-Bøjsøe C;Meyre D;Wheeler E;Ong K;Nohr EA;Vrijkotte TGM;Koppelman GH;Plomin R;Njølstad PR;Dedoussis GD;Froguel P;Sørensen TIA;Jacobsson B;Freathy RM;Zemel BS;Raitakari O;Vrijheid M;Feenstra B;Lyytikäinen LP;Snieder H;Kirsten H;Holt PG;Heinrich J;Widén E;Sunyer J;Boomsma DI;Järvelin MR;Körner A;Davey Smith G;Holm JC;Atalay M;Murray C;Bisgaard H;McCarthy MI;Early Growth Genetics Consortium;Jaddoe VWV;Grant SFA;Felix JF
• 通讯作者: Felix JF