MADD

From influencing how our body stores fat to how our brain regulates appetite, hundreds of genes, along with environmental factors, collectively determine our weight and body size. Now, researchers add several genes, which appear to affect obesity risk in certain sexes and ages, to that list. The study may shed light on new biological pathways that underlie obesity and highlight how sex and age contribute to health and disease. From influencing how our body stores fat to how our brain regulates appetite, hundreds of genes, along with environmental factors, collectively determine our weight and body size. Now, researchers add several genes, which appear to affect obesity risk in certain sexes and ages, to that list. The study, published on August 2 in the journal Cell Genomics, may shed light on new biological pathways that underlie obesity and highlight how sex and age contribute to health and disease. "There are a million and one reasons why we should be thinking about sex, age, and other specific mechanisms rather than just lumping everyone together and assuming that disease mechanism works the same way for everyone," says senior author John Perry, a geneticist and professor at the Wellcome-MRC Institute of Metabolic Science, University of Cambridge, U.K. "We're not expecting people to have completely different biology, but you can imagine things like hormones and physiology can contribute to specific risks." To untangle sex's role in obesity risk, the research team sequenced the exome -- the protein-coding part of the genome -- of 414,032 adults from the UK Biobank study. They looked at variants, or mutations, within genes associated with body mass index (BMI) in men and women, respectively. Based on height and weight, BMI is an estimated measurement of obesity. The search turned up five genes influencing BMI in women and two in men. Among them, faulty variants of three genes -- DIDO1, PTPRG, and SLC12A5 -- are linked to higher BMI in women, up to nearly 8 kg/m² more, while having no effect on men. Over 80% of the women with DIDO1 and SLC12A5 variants had obesity, as approximated by their BMI. Individuals carrying DIDO1 variants had stronger associations with higher testosterone levels and increased waist-to-hip ratio, both risk indicators for obesity-related complications like diabetes and heart disease. Others with SLC12A5 variants had higher odds of having type 2 diabetes compared with non-carriers. These findings highlight previously unexplored genes that are implicated in the development of obesity in women but not men. Perry and his colleague then repeated their method to look for age-specific factors by searching for gene variants associated with childhood body size based on participants' recollections. They identified two genes, OBSCN and MADD, that were not previously linked to childhood body size and fat. While carriers of OBSCN variants had higher odds of having higher weight as a child, MADD variant carriers were associated with smaller body sizes. In addition, the genetic variants acting on MADD had no association with adult obesity risk, highlighting age-specific effects on body size. "What's quite surprising is that if you look at the function of some of these genes that we identified, several are clearly involved in DNA damage response and cell death," says Perry. Obesity is a brain-related disorder, whereas biological and environmental factors act to influence appetite. "There's currently no well-understood biological paradigm for how DNA damage response would influence body size. These findings have given us a signpost to suggest variation in this important biological process may play a role in the etiology of obesity." Next, the research team hopes to replicate the study in a larger and more diverse population. They also plan to study the genes in animals to peer into their function and relationship with obesity. "We're at the very earliest stages of identifying interesting biology," says Perry. "We hope the study can reveal new biological pathways that may one day pave the way to new drug discovery for obesity."

研究团队提出了11p11.2基因座“多变异-多基因协同贡献AD遗传易感风险”的假说，即一个统计信号提示的风险基因座内有多个功能变异，调控了该基因座内多个基因的表达改变，进而协同贡献于AD的发病风险。 阿尔茨海默病（AD）是老年神经退行性疾病。阿尔茨海默病的发生发展受多种遗传因素的影响。目前，基于大规模病人-对照人群的遗传学研究，特别是全基因组关联分析（GWAS），已鉴定到近百个可靠的AD遗传风险相关基因座（loci），为AD发病机制研究和药物靶点发掘提供了契机。然而，大部分基因座包括几十到上百个紧密连锁的、统计学相关的非编码区变异和多个表达高度相关的基因，从中识别真正具有生物学效应、与疾病发病相关的变异（功能变异，causal variant）和基因（致病基因，causal gene）是AD遗传学研究的热点和难点。 11p11.2基因座位于11号染色体短臂，长度约为1.5 Mb，覆盖400多个AD相关变异和约50个基因，是最为复杂的AD风险相关基因座之一。按照传统观点，一个疾病风险相关信号的基因座可能提示一个致病基因。然而，前人针对11p11.2基因座的致病基因鉴定难以得到一致结论。事实上，疾病风险基因座的致病基因定位研究，缺乏系统的、理论性的研究范式。中国科学院昆明动物研究所研究员姚永刚及张登峰团队，致力于AD的遗传机制研究。研究前期分析发现，虽然11p11.2在GWAS中属于同一个统计关联信号，但该基因座内的AD相关变异位于多个彼此独立且效应方向不同的遗传连锁群，并与多个基因表达相关，因而推测一个风险基因座可能指向多个独立的致病信号。为了验证这一猜想，该团队开展了系统的功能基因组学筛选和功能实验研究。 通过整合AD相关大规模GWASs、脑组织和神经细胞的组蛋白修饰、染色质开放状态、转录因子结合等多个层面的组学数据，研究从11p11.2基因座数百个变异位点中鉴定到24个（而非1个）潜在的功能变异。这些变异可能通过影响其所在调控元件与转录因子的结合，进而调控靶基因的表达；使用独立的整合算法表明该风险基因座中存在多个功能变异和效应基因。等位基因特异性表达分析和双荧光报告实验进一步证明上述变异确实是功能变异。进而，结合基因表达调控、三维染色质互作、单碱基编辑和染色质可及性测序，研究发现这些功能变异能够通过长距离染色质作用，同时调控多个靶基因的表达。为确认这些靶基因的表达改变确实参与AD发生，而不是基因表达调控多效性所致，该团队开展了进一步的分析和实验。研究发现，与统计分析和表达调控结果一致，受这些功能变异调控的6个潜在致病基因（MTCH2、ACP2、NDUFS3、PSMC3、C1QTNF4和MADD）的组蛋白修饰、mRNA和蛋白水平在AD患者脑组织存在表达改变；在胶质细胞系中敲降或过表达这些潜在致病基因则发现，这些基因的表达改变均能够影响AD核心病理分子淀粉样蛋白Aβ和磷酸化Tau蛋白水平，提示这些潜在致病基因或参与AD的发病进程。 研究团队提出了11p11.2基因座“多变异-多基因协同贡献AD遗传易感风险”的假说，即一个统计信号提示的风险基因座内有多个功能变异，调控了该基因座内多个基因的表达改变，进而协同贡献于AD的发病风险。这一假说适用于11p11.2，或同样适用于其他具有复杂连锁和表达调控模式的疾病风险基因座。该成果有望为AD诊治提供新的思路和靶标，并为遗传变异贡献于复杂性状的机制研究尤其是统计模型的开发，提供概念和范式上的创新。 相关研究成果以Coexistence of multiple functional variants and genes underlies genetic risk locus 11p11.2 of Alzheimer’s disease为题，发表在《生物精神病学》（Biological Psychiatry）上。研究工作得到国家自然科学基金委员会、科学技术部、中国科学院和云南省的支持。