Seasonality of Mood: A Genome-Wide Association Study in the Old Order Amish

描述(申请人提供)：由于自然光的季节性变化，许多动物在生理和行为上表现出明显的季节性变化，例如与冬眠、繁殖和迁徙有关的变化。虽然人类与世隔绝的程度越来越高(但远未完全)，但某些个体在情绪和行为上表现出季节性变化，尽管程度比光周期动物要温和。一些复发性情绪障碍患者在秋季或冬季发展为完全的主要抑郁综合征，并在春季或夏季完全缓解，这种情况被称为季节性情感障碍冬季类型(SAD)。SAD是一种与间歇性但严重的职业、学习和社会功能损害有关的疾病。尽管对于治疗SAD的专业人员来说，秋季和冬季的心理社会困难是迫在眉睫的，但这种疾病的生物学本质强调了这种疾病的生物学本质，即某些SAD症状与光周期哺乳动物的特定季节行为变化(环境脱离、食欲增加、体重和嗜睡、能量和生殖动力下降)24、定时强光暴露在治疗SAD27-30方面的有效性，SAD患者(但不是光周期哺乳动物)冬季夜间褪黑激素分泌持续时间延长1先前使用季节性模式评估问卷(SpaQ)进行的双胞胎季节性研究给出了全球季节性评分(GSS)，报告称情绪季节性的遗传度为29%%2。PI的长期目标是研究物理、化学和生物环境中加剧易患情绪障碍的物理、化学和生物环境中的沉淀和永久因素，更具体地说，确定季节性情绪和行为障碍的触发-易损性对。这个项目的短期目标是确定与情绪季节性相关的基因变异。我们将把SpaQ邮寄给1800名之前对500K或1M Affymetrics SNP芯片进行基因分型的阿米什参与者。GSS水平经对数转换并根据年龄和性别进行调整后，将分析遗传力，并使用混合模型方差分量来筛选与SNPs的关联，以考虑家族关系。然后，将在1000名立即获得DNA的亚米希人参与者中复制“最热门”的数据。根据研究小组和阿米什人之间的长期合作伙伴关系，问卷回复率预计将超过80%。这项研究在遗传和环境流行病学领域都是新颖的；从遗传上讲，这将是情绪季节性的第一个GWAs；在环境上，这将是第一个关于主要不使用电力的人群中情绪季节性的研究，因此，对自然光周期变化的暴露和调整更多。该项目预计将有助于设计未来关于SAD的研究，通过与新兴候选基因的相互作用，对情绪和光照暴露进行前瞻性测量。这可能会导致进一步的研究，最终可能导致SAD的个体化治疗，并可能促进我们对导致情绪、行为和心血管风险因素季节性变化的机制的了解，如体重、胆固醇和免疫介质，这些因素被怀疑是导致冬季心血管死亡率增加的原因。 公共卫生相关性：季节性情感障碍，也称为SAD/冬季抑郁症，是一种影响数百万美国人的严重疾病；我们建议对1000名阿米什人进行情绪季节性测试，这些人之前曾为另一项研究分析过他们的全基因组，而且他们的习俗不允许使用电力，减少冬季暴露在人造光下，夏天使用空调。根据K18的使命，这笔赠款将帮助申请者熟练掌握全基因组方法，这将为他正在进行的情绪障碍和自杀行为环境诱因的脆弱性探索增加重大能力，这些领域是公共卫生优先领域。这项研究将是第一个关于情绪季节性的基因组研究，也是美国第一个在不使用电灯的人群中进行的季节性研究。

DESCRIPTION (provided by applicant): In response to and in anticipation of seasonal changes in natural- light, many animals manifest marked seasonal changes in physiology and behavior, such as those related to hibernation, breeding and migration. Although humans have increasingly (but far from completely) isolated themselves from the natural environment, certain individuals manifest seasonal changes in mood and behavior, though to more modest degree than in photoperiodic animals. Some patients with recurrent mood disorders develop full major depression syndromes in the fall or winter, with full remission in spring or summer, a condition called seasonal affective disorder winter type (SAD). SAD is a condition associated with an intermittent but significant impairment in occupational, academic and social functioning. Although psychosocial difficulties in fall and winter are in the immediate picture for professionals treating SAD, the biological nature of this condition is underscored by similarities in certain SAD symptoms with season-specific behavioral changes in photoperiodic mammals (environment disengagement, increased appetite, weight and sleepiness, reduced energy and reproductive drive)24, the effectiveness of timed bright light exposure in treating SAD27-30, and an extended duration in winter of nocturnal melatonin secretion in SAD patients (but not in controls) as in photoperiodic mammals1 A previous twin study on seasonality using the Seasonal Pattern Assessment Questionnaire (SPAQ) that gives a global seasonality score (GSS) has reported that the heritability of seasonality of mood is 29%% 2. The long term objective of the PI is to study precipitating and perpetuating factors in the physical, chemical and biological environment exacerbating mood disorders in predisposed individuals, and more specifically to identify trigger- vulnerability pairs for seasonal disturbances in mood and behavior. The short term objective of this project is to identify genetic variations that are associated with seasonality of mood. We will mail the SPAQ to 1800 Amish participants previously genotyped for the 500K or 1 M Affymetrics SNP chip. GSS levels, logarithm-transformed and adjusted for age and sex, will be analyzed for heritability and screened for association with SNPs using mixed model variance components to account for familial relatedness. The "top hits" will then be replicated in 1,000 Amish participants in whom DNA is immediately available. The questionnaire response rate is expected to exceed 80%, based on long standing partnership between the research team and the Amish. This study will be novel in both genetic and environmental epidemiology domains; genetically this will be the first GWAS of mood seasonality, and environmentally, the first study of seasonality of mood in a population that predominantly does not use electricity, thus, with greater exposure and tuning to natural photoperiodic changes. The project is expected to contribute to designing future studies on SAD, with prospective measurements of mood and light exposure, in interaction with emerging candidate genes. This may lead to further studies that may ultimately result in individualized treatment of SAD, as well as potentially advance our knowledge on mechanisms leading to seasonal variation in mood, behavior and cardiovascular risk factors, such as weight, cholesterol, and immune mediators, suspected to contribute to increased cardiovascular mortality in the winter. PUBLIC HEALTH RELEVANCE: Seasonal affective disorder, also called SAD /winter depression, is a serious condition that affects millions of Americans; we propose to perform obtain a score of mood seasonality in 1000 Amish subjects who had their full genome previously analyzed for another study and whose customs do not allow use of electricity reducing exposure to artificial light in winter and use of air conditioners in summer. In line with the mission of K18, This grant will help the applicant to become fluent with full genome approaches that will add a major capability to his ongoing exploration of vulnerabilities to environmental triggers in mood disorders and suicidal behavior, domains of public health priority. The study will be the first genomic study on seasonality of mood, and first seasonality study in the US in a population not using electric light.