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

描述（由申请人提供）：为了应对和预测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。尽管人类越来越多地（但远不是完全）将自己与自然环境隔离开来，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得多。一些反复发作的情绪障碍患者在秋季或冬季出现完全的重度抑郁综合征，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型（SAD）。SAD是一种与间歇性但显著的职业、学业和社会功能障碍相关的疾病。虽然秋季和冬季的社会心理困难是治疗SAD的专业人员的直接画面，但这种情况的生物学性质强调了某些SAD症状与光周期哺乳动物的季节特定行为变化的相似性（环境脱离，食欲，体重和嗜睡增加，能量和生殖动力下降）24，在治疗SAD时的强光照射的有效性27-30，和光周期哺乳动物一样，SAD患者冬季夜间褪黑素分泌的持续时间延长（但对照组没有）1 .先前使用季节性模式评估问卷（SPAQ）对季节性进行的双胞胎研究给出了全球季节性评分（GSS），该研究报告称，情绪季节性的遗传率为29%% 2。PI的长期目标是研究物理、化学和生物环境中加剧易感个体情绪障碍的促发和持久因素，更具体地说，是确定情绪和行为季节性紊乱的触发-脆弱性对。该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名阿米什人，他们之前已经为500K或1m Affymetrics SNP芯片进行了基因分型。GSS水平经过对数转换，并根据年龄和性别进行调整，将分析遗传力，并使用混合模型方差成分筛选与snp的关联，以解释家族相关性。然后，“最热门的”将在1000名阿米什人身上复制，他们的DNA可以立即获得。基于研究小组与阿米什人的长期合作关系，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；从遗传学上讲，这将是第一个情绪季节性的GWAS，从环境上讲，这是第一个在主要不使用电力的人群中进行的情绪季节性研究，因此，更多的暴露和调整自然光周期变化。该项目有望有助于设计未来的SAD研究，包括情绪和光照的前瞻性测量，以及与新出现的候选基因的相互作用。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，并有可能提高我们对导致情绪、行为和心血管危险因素（如体重、胆固醇和免疫介质）季节性变化的机制的认识，这些因素被怀疑是导致冬季心血管死亡率增加的原因。

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.