Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults.
Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults.
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DOI：
10.1371/journal.pgen.1005573
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发表时间：
2015-10
期刊：
影响因子：
4.5
通讯作者：
Siscovick DS
中科院分区：
文献类型：
--
作者：
Hochner H;Allard C;Granot-Hershkovitz E;Chen J;Sitlani CM;Sazdovska S;Lumley T;McKnight B;Rice K;Enquobahrie DA;Meigs JB;Kwok P;Hivert MF;Borecki IB;Gomez F;Wang T;van Duijn C;Amin N;Rotter JI;Stamatoyannopoulos J;Meiner V;Manor O;Dupuis J;Friedlander Y;Siscovick DS
在心脏代谢性状的全基因组关联研究（GWAS）中发现的基因座占性状遗传力的一小部分。到目前为止，大多数相关研究都没有考虑原产地效应（POE）。在这里，我们报告调查的POEs对肥胖和血糖性状的年轻人。耶路撒冷围产期家庭随访研究（JPS），包括1250名年轻人和他们的母亲被用于发现。聚焦于先前GWAS确定的与心脏代谢特征相关的18个基因，我们使用线性回归来检查母体和父源后代次要等位基因与体重指数（BMI）、腰围（WC）、空腹血糖和胰岛素的相关性。我们在来自Frachial Heart研究、家族心脏研究和Erasmus鲁克芬家族研究（总人数4800）的家系中，对年龄≤50岁的欧洲血统个体的JPS结果进行了复制和荟萃分析。我们认为p<2.7x10-4具有统计学显著性，以解释多重检验。我们在APOB第4外显子中发现了一个共同的编码变异（rs 1367117），该变异对BMI（β = 0.8; 95%CI：0.4，1.1; p = 3.1x10-5）和WC（β = 2.7; 95%CI：1.7，3.7; p = 2.1x10-7）具有显著的母源性影响。相应的父亲来源的影响不显着（p>0.6）。观察到rs 1367117与空腹血糖（β = 0.9; 95%CI：0.3，1.5; p = 4.0x10-3）和胰岛素（ln-转换，β = 0.06; 95%CI：0.03，0.1; p = 7.4x10-4）之间存在暗示性的母体相关性。rs 1367117的生物信息学注释揭示了该区域在肝脏和脂肪组织中的多种调节功能，并且仅在肝脏中具有50%的甲基化模式，与等位基因特异性甲基化一致，这可能表明组织特异性POE。我们的研究结果表明，一种常见的APOB变异体与肥胖之间存在母亲特异性关联，这种关联以前在GWAS中未检测到。这些结果为调节机制，特别是POEs在肥胖中的作用提供了证据。此外，这项研究强调了利用家庭研究破译复杂性状的遗传结构的好处。迄今为止，利用最新技术和方法学进展在大规模遗传研究中发现的遗传变异只能解释肥胖、糖尿病和其他心血管风险因素的一小部分遗传基础。这些研究通常在无关个体的样本中进行。在这里，我们利用一个家庭为基础的方法来确定与肥胖相关的性状的遗传变异。具体来说，我们研究了母系与父系遗传的常见遗传变异对这些特征的单独贡献。通过检查1250年轻人和他们的母亲从耶路撒冷，我们表明，一个特定的遗传变异，rs 1367117，位于2号染色体上的APOB基因与体重指数和腰围时，从母亲遗传，而不是从父亲。这种母性效应并不局限于Jeremiemites，但也出现在来自世界各地独立家庭研究的欧洲血统个体的大样本中。我们的研究结果为复杂的遗传机制在肥胖中的作用提供了支持，并强调了利用家族研究揭示常见风险因素和疾病的遗传途径的好处。
Loci identified in genome-wide association studies (GWAS) of cardio-metabolic traits account for a small proportion of the traits' heritability. To date, most association studies have not considered parent-of-origin effects (POEs). Here we report investigation of POEs on adiposity and glycemic traits in young adults. The Jerusalem Perinatal Family Follow-Up Study (JPS), comprising 1250 young adults and their mothers was used for discovery. Focusing on 18 genes identified by previous GWAS as associated with cardio-metabolic traits, we used linear regression to examine the associations of maternally- and paternally-derived offspring minor alleles with body mass index (BMI), waist circumference (WC), fasting glucose and insulin. We replicated and meta-analyzed JPS findings in individuals of European ancestry aged ≤50 belonging to pedigrees from the Framingham Heart Study, Family Heart Study and Erasmus Rucphen Family study (total N≅4800). We considered p<2.7x10-4 statistically significant to account for multiple testing. We identified a common coding variant in the 4th exon of APOB (rs1367117) with a significant maternally-derived effect on BMI (β = 0.8; 95%CI:0.4,1.1; p = 3.1x10-5) and WC (β = 2.7; 95%CI:1.7,3.7; p = 2.1x10-7). The corresponding paternally-derived effects were non-significant (p>0.6). Suggestive maternally-derived associations of rs1367117 were observed with fasting glucose (β = 0.9; 95%CI:0.3,1.5; p = 4.0x10-3) and insulin (ln-transformed, β = 0.06; 95%CI:0.03,0.1; p = 7.4x10-4). Bioinformatic annotation for rs1367117 revealed a variety of regulatory functions in this region in liver and adipose tissues and a 50% methylation pattern in liver only, consistent with allelic-specific methylation, which may indicate tissue-specific POE. Our findings demonstrate a maternal-specific association between a common APOB variant and adiposity, an association that was not previously detected in GWAS. These results provide evidence for the role of regulatory mechanisms, POEs specifically, in adiposity. In addition this study highlights the benefit of utilizing family studies for deciphering the genetic architecture of complex traits. To date, genetic variants identified in large-scale genetic studies using recent technical and methodological advances explain only a small proportion of the genetic basis of obesity, diabetes and other cardiovascular risk factors. These studies were typically conducted in samples of unrelated individuals. Here we utilize a family-based approach to identify genetic variants associated with obesity-related traits. Specifically, we examined the separate contribution of maternally- vs. paternally-inherited common genetic variants to these traits. By examining 1250 young adults and their mothers from Jerusalem, we show that a specific genetic variant, rs1367117, located in the APOB gene on chromosome 2 is related to body mass index and waist circumference when inherited from mother and not from father. This maternal effect is not restricted to Jerusalemites, but is also seen in a large sample of individuals of European descent from independent family studies worldwide. Our findings provide support of the role of complex genetic mechanisms in obesity, and highlight the benefit of utilizing family studies for uncovering genetic pathways underlying common risk factors and diseases.