Differences between the sexes among genetic variants affecting orofacial cleft birth defect risk

影响口颌裂出生缺陷风险的基因变异的性别差异

• 批准号: 10420286
• 负责人: Mary L. Marazita
• 金额: $ 41.55万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-05 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10420286
• 关键词: Accounting; Affect; African; Anatomy; Asian population; Birth; CDH1 gene; Cleft Lip; Cleft Palate; Cleft lip with or without cleft palate; Collection; Complex; Congenital Abnormality; Craniofacial Abnormalities; Data; Databases; Detection; Epidemiology; Ethnic group; Etiology; European; Family; Family Study; Female; Genes; Genetic; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetic study; Genome Scan; Genomics; Genotype; Heritability; Heterogeneity; Human; Infant; Link; Live Birth; Methods; Nonsense Mutation; Nucleotides; Parents; Partner in relationship; Pattern; Penetrance; Play; Population; Prevalence; Procedures; Recording of previous events; Reporting; Research; Risk; Role; Sex Differences; Subgroup; Suggestion; Syndrome; Testing; Twin Studies; Validation; Variant; X Chromosome; autosome; base; causal variant; cleft lip and palate; de novo mutation; design; follow-up; genetic architecture; genetic pedigree; genetic variant; genome wide association study; genome-wide analysis; genomic data; in silico; male; malformation; multi-ethnic; novel; orofacial cleft; population based; proband; rapid testing; rare variant; risk sharing; sex; trait; transmission process

PROJECT SUMMARY Orofacial clefts (OFCs) represent the most common group of craniofacial malformations in humans affecting approximately one per 1,000 live births worldwide. OFCs include cleft lip (CL), cleft palate (CP) and cleft lip with cleft palate (CLP), which can occur as isolated malformations, with another malformation or as part of a recognized malformation syndrome (often Mendelian with incomplete penetrance). OFCs are commonly categorized into two anatomically and embryologically distinct entities based on embryologic and epidemiologic patterns: cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP). Among all infants born with an OFC, 70 percent of CL/P cases and 50 percent of CP cases occur as isolated, non-syndromic malformations. Non-syndromic CL/P occurs more frequently in males than females (ratio 2:1) whereas non-syndromic CP occurs more often in females (ratio approximately 1:1.14). Substantial variation in birth prevalence rates of non- syndromic CL/P has been reported across populations, with Asian populations having higher birth prevalence rates compared to European populations, and African populations having the lowest birth prevalence rates. Risk to OFC shows strong evidence of genetic control with estimated heritability up to 90%. Recent genome- wide association studies have clearly shown multiple genes play a role in the etiology of OFCs, but with substantial heterogeneity among families and across populations. To date, approximately 50 different genes have been identified as significant in such genome-wide studies of OFCs, with about two dozen having substantial replication and/or functional studies. However, despite a long history of scientific research into the genetic control of OFC, much of the heritability remains unexplained (which may reflect the genetic heterogeneity influencing risk to OFC, where a number of different genes with both rare and common variants control risk), and it remains difficult to clearly identify underlying causal genes. Moreover, sex differences in risk to OFC and parent-of-origin effects traditionally have not been the focus of genetic studies, and X chromosome variants have largely been ignored. In this application, we are using existing genomic data from family-based studies in different ethnic groups to specifically study the underlying mechanisms for differential risk to OFC between the sexes. Specifically, we will (i) use case-parent trios to detect different genetic OFC risk effect sizes and parent of origin effects, (ii) use a novel method to characterize sex differences in the genetic architecture of OFCs accounting for potential cleft type differences and similarities, and (iii) conduct association tests for variants on the X chromosome. In addition, we will use genomic data from extended multiplex pedigrees to identify highly penetrant genomic X-linked variants. The family-based designs allow us to study common and rare variants, parent-of origin effects, and allow us to assess the impact of de novo variants. In all aims, we will attempt to use functional data from external data bases to conduct an “in silico” validation of our findings.

项目摘要 口面裂口（OFC）代表了影响人类的最常见的颅面畸形群 全世界大约有1000个活产。 OFC包括唇裂（CL），cl裂（CP）和唇裂。 left的口感（CLP），可以作为孤立的畸形，另一种畸形或作为一部分 公认的畸形综合征（通常具有不完全渗透率的门德利人）。 OFC通常是 基于胚胎学和流行病学，分为两个解剖学和胚胎学上的实体 图案：单独使用或不带裂口的唇裂（Cl/p）和left裂（CP）。在所有出生的婴儿中 OFC，有70％的CL/P病例和50％的CP病例作为孤立的非综合畸形发生。 与女性相比，非合成cl/p的发生频率比女性更频繁（比率2：1），而非综合症CP发生 女性的经常（大约1：1.14）。非 - 出生患病率的实质性差异 据报道，综合征CL/P在人群中，亚洲人群的出生率较高 与欧洲人口相比，比率和非洲人口的出生率最低。 OFC的风险显示出有力的遗传控制证据，估计遗传力高达90％。最近的基因组 - 广泛的关联研究清楚地表明，多个基因在OFC的病因中起作用，但与 家庭和人口之间的实质异质性。迄今为止，大约50个不同的基因 在此类OFC的此类基因组研究中已被确定为重要 大量复制和/或功能研究。然而，尽管科学研究历史悠久 OFC的遗传控制，许多遗传力仍然无法解释（这可能反映了遗传异质性 影响OFC的风险，其中许多具有稀有和常见变体的不同基因控制风险），以及 很难清楚地识别潜在的因果基因。此外，OFC和OFC风险的性别差异和 传统上，产卵的父母效应不是遗传研究的重点，X染色体变体具有 在很大程度上被忽略了。在此应用中，我们使用了来自不同家庭研究的现有基因组数据 种族群体专门研究男女之间OFC的不同风险的基本机制。 具体而言，我们将（i）使用案例三个三重点来检测不同的遗传OFC风险效应和原始父母 效果，（ii）使用一种新颖的方法来表征OFCS会计遗传结构中的性别差异 对于潜在的裂口类型差异和相似性，以及（iii）进行X上变体的关联测试 染色体。此外，我们将使用来自扩展的多重谱系的基因组数据来高度识别 渗透基因组X连锁变体。基于家庭的设计使我们能够研究常见和稀有变体， 父母的起源效果，并允许我们评估从头变体的影响。总的来说，我们将尝试使用 来自外部数据基础的功能数据对我们的发现进行“计算机”验证。