健康与遗传心理学研究室知识库

公平是对人类社会生活中的行为起到关键作用的一种规范，既有利于良好人际关系的建立，又有利于推进社会合作的达成。源于博弈论的最后通蝶博弈(Ultimatum Game, UG)范式是实验室常用的研究公平及其相关决策行为的实验范式。众所周知，人类的行为是由遗传和环境因素共同作用的结果。基于公平行为的文化和进化起源讨论，研究者提出公平相关决策行为可能具有一定的遗传和环境基础。近期的双生子研究发现了证据，支持公平相关决策行为的个体差异受遗传因素的影响，但影响公平相关决策行为的候选基因还有待进一步确定。另一方面，研究者利用脑影像学技术(如功能磁共振成像技术)发现了人类在对公平和不公平的方案进行加工时和做出公平决策行为时的神经基础。但是这些以往的研究并没有明确地建立公平背后的神经活动与决策行为个体差异之间的关联。也不清楚，公平(不公平)诱发脑活动的个体差异是否会受遗传因素影响。此外，目前还不清楚遗传因素，比如多巴胺和5-经色胺系统基因多态性，如何通过影响脑活动或者脑区交互活动来影响公平相关决策行为。因此，本研究计划采用基于最后通蝶博弈的研究范式，采用影像遗传学的研究方法，研究遗传因素(多巴胺能和5-经色胺能通路基因多态性)对公平决策行为及其脑活动的影响，以期从基因-脑一行为角度获得对公平决策及其生理基础的综合理解。

为了实现以上目的，本博士学位论文结合双生子研究和基于单核普酸多态性(single nucleotide polymorphism, SNP)的遗传关联分析研究的影像遗传学研究方法，通过四个研究来考察了遗传因素与公平决策行为及其神经基础之间的关系。

研究一包含两个子研究。我们首先采用双生子研究的方法，研究了最后通蝶博弈中回应者行为的遗传性。该研究纳入了100对双生子(同卵52对，异卵48对)作为回应者来参与最后通蝶博弈，采用单变量遗传模型来分析遗传和环境因素对于被试拒绝率的贡献。研究发现:被试对于更不公平方案的拒绝率受到中等程度的遗传影响(30%-34%，被试对于更公平方案的拒绝率则主要受到环境因素的影响。进一步，我们采用基于SNP的遗传关联分析研究的方法，考察了多巴胺能和5-经色胺能通路几个候选基因的基因多态性对最后通蝶博弈中回应者拒绝行为的影响。研究发现，色氨酸经化酶(tryptophan hydroxylase, TPH)第二个亚型TPH2 (rs4570625)位点的基因多态性显著影响最后通蝶博弈中回应者对不公平分配方案的拒绝率，具体表现为更为不公平的条件下G/G基因型和G/T基因型个体的拒绝率高于T/T基因型个体，但更为公平的条件下三种基因型个体的拒绝率相接近。

研究二包含两个子研究。我们首先采用双生子研究的方法，研究了最后通蝶博弈中公平(不公平)诱发脑活动的遗传性。被试(同研究一)在参与最后通蝶博弈的同时进行fNIRI扫描。通过采用双生子单变量遗传模型来分析遗传和环境因素对于公平(不公平)诱发脑活动的贡献，我们发现遗传因素对不公平方案所诱发的前扣带回的脑活动有中等程度的贡献(37%-55%。进一步，我们采用基于SNP的遗传关联分析研究的方法，研究TPH2 (rs4570625)位点基因多态性对公平 (不公平)诱发脑活动的影响，但是没有发现不同基因型被试在任务诱发脑活动上的显著差异。

研究三试图建立公平(不公平)诱发脑活动与拒绝率个体差异的关系。我们发现在不同公平性水平下背侧前扣带和双侧脑岛等脑区活动差异更大的个体，他们的拒绝率更低。进一步，我们按拒绝率将被试分为高、中、低拒绝率三组时，组间比较发现，高拒绝率的个体与低拒绝率和中拒绝率的个体的脑激活模式存在显著差异，主要表现为低拒绝率和中拒绝率组在背侧前扣带和内侧前额叶、双侧脑岛、左侧额中回、左侧顶下小叶、双侧视觉皮层等脑区存在激活差异，但是高拒绝率组只在背内侧前额叶存在显著激活差异。

研究四试图从基因一脑一行为的角度探索5-经色胺通路TPH2 (rs4570625)位点基因多态性与公平的神经基础以及拒绝率个体差异之间的关系。从脑激活角度，我们发现公平对右侧背侧前扣带脑活动的调节作用会表现出受基因多态性和拒绝率交互作用影响的趋势，即在不同基因型组别中，公平对右侧背侧前扣带脑活动的调节作用和拒绝率相关模式不同。从脑区功能交互角度，我们采用动态因果模型和参数经验贝叶斯的分析技术，构建了一个包含背侧前扣带、双侧脑岛、左侧背外侧前额叶的脑网络，发现TPH2 (rs4570625)位点基因多态性与拒绝率的交互作用对分配方案呈现时脑区间效应连接有显著的调节作用。

总之，本博士论文使用影像遗传学的研究方法，发现了最后通蝶博弈中回应者拒绝行为受中等程度的遗传因素影响并且5-}z色胺通路TPH2 (rs4570625)位点的基因多态性可能是造成这种个体差异的原因之一;发现公平(不公平)诱发的前扣带回脑活动的个体差异受中等程度的遗传因素影响;发现前扣带回、双侧脑岛等脑区受分配方案公平性水平影响的程度和个体的拒绝率显著相关;进一步，由前扣带回、脑岛和背外侧前额叶构成的脑网络中脑区间效应连接和个体拒绝率之间的关系受5-经色胺通路TPH2 (rs4570625)位点基因多态性的调节。这些发现帮助我们从基因一脑一行为角度获得对公平决策及其生理基础的综合理解，并为公平决策候选基因的选择提供科学依据。

Fairness is a norm that plays a key role in the behavior of human social life. It is conducive to the establishment of good interpersonal relationships and beneficial to the promotion of social cooperation. The Ultimatum Game (UG) paradigm, derived from game theory, is an experimental paradigm commonly used in laboratories to study fairness-related decision-making behaviors. It is well known that all behavior is the joint product of heredity and environment. Based on the discussing of the cultural and evolutionary origins of fairness behavior, researchers suggested that there are genetic and environmental basis for fairness. Recently, twin studies and neurogenetic researches provided evidences for that individual difference of responder's behavior is heritable. But the candidate genes that influence fairness-related decision-making behavior remain to be further determined. On the other hand, scientists have used neuroimaging technique (such as functional magnetic resonance imaging, fMRI) to achieve better understanding of the neural basis when we are making fairness-related decisions. However, in previous studies, the relationship between the neural activities and the individual difference of fairness-related decision-making behaviors was not clearly established. While, whether the individual difference of the activities of the brain regions involved in the fairness-related decision-making will also have a genetic contribution, this question has not been clearly answered. In addition, the genetic factors' (such as the genetic polymorphisms of dopaminergic and serotonin systems) specific impact of how to influence the fairness-related decision-making behavior by influencing the brain activity or brain interaction has not been fully understood. Therefore, applying an imaging genetics approach, the current research adopted the UG paradigm and fMRI technique to study the genetic (such as dopaminergic and 5-hydroxytryptamine pathway gene polymorphism) influence on fairness-related decision-making behaviors and its brain activities. We aimed to obtain a comprehensive understanding of the fairness-related decision-making and its physiological basis from the perspective of gene-brain-behavior.

In order to achieve the above objectives, this Ph.D. thesis adopted imaging genetics research methods (combining twin studies and single nucleotide polymorphism (SNP)-based association analysis studies) to examine the relationship among genetic factors, fairness-related decision-making behavior and its physiological basis.

Study 1 included two sub-studies. We first used the twin design to investigate the behavior in the UG. The study included 100 pairs twins (52 pairs of monozygotic twins, 48 pairs of dizygotic twins) as responders. The univariate genetic model was fitted to test the contributions of genetic and environmental factors to the rejection rate of the participants. This study found that: (1) the rejection rate for the more unfair proposals was moderately heritable (30%-34%), while for the fairer proposals, the rejection rate was mainly affected by environmental factors (66%一70%). Next, in the SNP-based association analysis study, we investigated the effects of the polymorphisms of the dopaminergic and 5-hydroxytryptamine (5-HT) pathway genes on the rejection behavior in the UG. The study found that the gene polymorphism of the 5-HT pathway tryptophan hydroxylase TPH2 (rs4570625) significantly affected the responders' rejection rate to the unfair proposals in the UG. Specifically, under the more unfair conditions, the rejection rate of G/G genotype and G/T genotype individuals was higher than that of the T/T genotype individuals, but the rejection rates of the three genotype individuals were similar under fairer conditions.

Study 2 included two sub-studies. Firstly, we used the twin study method to investigate the heritability of brain activation induced by unfairness (fairness) in the UG. We conducted fMRI scans of the participants in the study 1 when they were playing the UG. The voxel-based univariate genetic model was fitted to estimate the contributions of genetic and environmental factors to the brain activation induced by unfairness (fairness) in the UG. In this study we found that: when comparing unfair with fair proposals, activation of dorsal anterior cingulate cortex (dACC) was moderately heritable (37%一55%). However, SNP-based association analysis study has not found that the polymorphism of TPH2 (rs4570625) affects the activation of the brain regions that are more strongly activated in unfair conditions.

In Study 3, we attempted to establish the association between brain activation induced by unfairness (fairness) and individual difference of rejection rate. We found that participants with greater differences in brain activities of dACC and bilateral insula and other regions among different levels of fairness had lower rejection rates. Then, we divided the participants into high, medium and low rejection rates groups. We also found that there was a significant difference of brain activation patterns between the individuals with high rejection rate and individuals with low or medium rejection rate. The low and the medium rejection rate groups showed activation differences in the dACC and medial prefrontal cortex, bilateral insula, left medial frontal gyrus, left inferior parietal lobe, bilateral visual cortex, etc. But for the high rejection group, there was a significant difference in activation of the dorsal medial prefrontal lobe.

In study 4, we tried to establish the relationship among the polymorphism of the 5-HT pathway TPH2 (rs4570625), the fairness-related decision-making brain activity and individual differences of rejection rates from a gene-brain-behavior perspective. First, we examined the activation of independent brain regions. Our study found a trend of that the interaction between the TPH2 (rs4570625) polymorphism and the rejection rate influences the fairness modulation effect on the right dACC. Among different genotype groups, there were different correlation patterns between the fairness modulation effect on the right dACC and the rejection behavior. Next, the brain network analysis (dynamic causal modeling and parametric empirical bayes) method was used to investigate the interaction of brain network including dACC, bilateral insula and left dorsolateral prefrontal cortex (DLPFC). The interaction between the TPH2 (rs4570625) polymorphism and the rejection rate can modulate the average effective connectivity among the brain regions during presentation of proposals.

In conclusion, this Ph.D. thesis uses imaging genetic method to find that: (1) the rejection behavior of UG was moderately affected by genetic influence, and the gene polymorphism of 5-HT pathway TPH2 (rs4570625) may be one of the causes of this individual difference; (2) the individual difference of dACC activation induced by unfairness (fairness) was moderately affected by genetic factor; (3) there was significant correlation between the individuals' rejection rates and the fairness modulation effect on the right dACC, bilateral insula, etc.;(4) the TPH2 (rs4570625) polymorphism modulated the interaction between the average effective connectivity among the network (including dACC, insula and left DLPFC) and the rejection rate. These findings help us to gain a comprehensive understanding of fairness-related decision-making and its physiological basis from a genetic-brain-behavior perspective, and to provide a scientific support for the selection of candidate genes for fairness-related decision-making.