检测与抑郁症相关基因的正选择信号-动脉网

Detection of positive selection on depression-associated genes

Nature 等信源发布 2025-03-13 10:52

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可切换为仅中文

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Abstract

摘要

Although depression significantly impacts fitness, some hypotheses suggest that it may offer a survival benefit. However, there has been limited systematic investigation into the selection pressures acting on genes associated with depression at the genomic level. Here, we conducted comparative genomic analyses and computational molecular evolutionary analyses on 320 depression-associated genes at two levels, i.e., across the primate phylogeny (long timescale selection) and in modern human populations (recent selection).

尽管抑郁症显著影响健康，但一些假设认为它可能具有生存优势。然而，对于在基因组水平上与抑郁症相关的基因所受到的选择压力，系统的调查仍然有限。在此，我们对320个与抑郁症相关的基因进行了比较基因组分析和计算分子进化分析，涵盖两个层面，即跨灵长类系统发育（长时间尺度选择）和现代人类群体（近期选择）。

We identified seven genes under positive selection in the human lineage, and 46 genes under positive selection in modern human populations. Most positively selected variants in modern human populations were at UTR regions and non-coding exons, indicating the importance of gene expression regulation in the evolution of depression-associated genes.

我们在人类谱系中鉴定出七个受到正选择的基因，并在现代人类群体中鉴定出46个受到正选择的基因。现代人类群体中大多数受到正选择的变异位于UTR区域和非编码外显子，这表明基因表达调控在抑郁症相关基因的演化中具有重要性。

Positively selected genes are not only related to immune responses, but also function in reproduction and dietary adaptation. Notably, the proportion of depression-associated genes under positive selection was significantly higher than the positively selected genes at the genome-wide average level in African, East Asian, and South Asian populations.

正向选择的基因不仅与免疫反应有关，还对生殖和饮食适应起作用。值得注意的是，在非洲、东亚和南亚人群中，与抑郁相关的正向选择基因的比例显著高于全基因组平均水平的正向选择基因。

We also identified two positively selected loci that happened to be associated with depression in the South Asian population. Our study revealed that depression-associated genes are subject to varying selection pressures across different populations. We suggest that, in precision medicine—particularly in gene therapy—it is crucial to consider the specific functions of genes within distinct populations..

我们还鉴定了两个正向选择的位点，它们恰好与南亚人群中的抑郁症相关。我们的研究揭示了抑郁症相关基因在不同人群中受到不同的选择压力。我们认为，在精准医学中，尤其是在基因治疗中，考虑基因在不同人群中的特定功能是至关重要的。

Introduction

简介

Depression ranks as the leading cause of disability and seriously affects the normal life of many people (Beurel et al.

抑郁症是导致残疾的首要原因，严重影响许多人的正常生活（Beurel等。

2020

). According to its typical clinical features, depression has multiple negative effects on human beings. The International Classification of Diseases (ICD-10-coded) defined depression as a mental disease in which

）。根据其典型的临床特征，抑郁症对人类有多方面的负面影响。《国际疾病分类》（ICD-10编码）将抑郁症定义为一种精神疾病，其中

the patient suffers from lowering of mood, reduction of energy, and decrease in activity. (Capacity for enjoyment, interest, and concentration is reduced, and marked tiredness after even minimum effort is common. Sleep is usually disturbed and appetite diminished. Self-esteem and self-confidence are almost always reduced and, even in the mild form, some ideas of guilt or worthlessness are often present.

患者情绪低落，精力减退，活动减少。（愉悦感、兴趣和专注能力下降，即使付出最小努力也会感到明显疲倦。睡眠通常受到干扰，食欲减退。自尊心和自信心几乎总是降低，即使在轻度形式下，也常存在一些内疚或无价值感的想法。）

The lowered mood varies little from day to day, is unresponsive to circumstances and may be accompanied by so-called “somatic” symptoms).

情绪低落几乎每天都没有什么变化，对环境没有反应，并且可能伴有所谓的“躯体”症状。

(

https://icd.who.int/browse10/2016/en#/F32

https://icd.who.int/browse10/2016/zh#/F32

). Recent studies have also reported that most suicides have been diagnosed with depression (Hawton et al.

）。最近的研究还报告称，大多数自杀者都被诊断出患有抑郁症（Hawton 等人。

2013

2013年

). In general, depression has considerable negative consequences, including notable costs to survival and fitness.

）。总体而言，抑郁症有相当大的负面影响，包括对生存和健康有显著的成本。

Although depression considerably impairs fitness, a few hypotheses propose that depression can have survival benefits. Some hypotheses focus on the phenotype of depression itself, emphasizing that emotions can affect physiological reactions and behavior, playing adaptive roles in social benefits, such as to reduce costly conflict and to avoid infection (Anders et al.

虽然抑郁症在很大程度上削弱了适应性，但一些假说提出抑郁症可能具有生存优势。一些假说聚焦于抑郁症本身的表型，强调情绪可以影响生理反应和行为，在社会利益方面发挥适应性作用，例如减少代价高昂的冲突以及避免感染（Anders等，）。

。

2013

). Other hypotheses emphasize the associations between depression and immune functions, such as the pathogen‒host defense hypothesis (Raison and Miller

）。其他假设强调了抑郁与免疫功能之间的关联，例如病原体‒宿主防御假设（Raison 和 Miller

2013

), which proposes that depression can help energy conservation and reallocation to enhance immune responses. To better understand the evolution of depression, we first need to systematically investigate the selection pressures on depression-associated genes at the genomic level.

），该假说认为抑郁有助于能量的保存和重新分配，从而增强免疫反应。为了更好地理解抑郁的演化，我们首先需要在基因组层面上系统地研究与抑郁相关基因的选择压力。

Natural selection is the major force driving the adaptive evolution of human beings, and selection pressures can occur at different stages during evolution. On the one hand, selection at the species level must be considered on a long timescale, i.e., millions of years and usually working on the decisive phenotypes for speciation.

自然选择是推动人类适应性进化的主要力量，选择压力可以在进化的不同阶段产生。一方面，物种层面的选择必须放在长时间尺度上考虑，即数百万年且通常作用于决定物种形成的表型。

For example, brain development and walking upright have been reported to be under positive selection in the human lineage (Wang and Crompton .

例如，据报道，大脑发育和直立行走在线粒体人类谱系中受到正向选择（Wang and Crompton）。

2004

2004年

; Dumas et al.

；杜马斯等

2021

). On the other hand, migration out of Africa in the last 100,000 years has further shaped different modern human populations under different selection pressures, including environmental changes, diversified food resources, and new pathogens (Benton et al.

）。另一方面，过去十万年间人类迁出非洲，不同的选择压力进一步塑造了不同的现代人类群体，包括环境变化、食物资源多样化以及新的病原体（Benton 等。

2021

). These recent selection pressures work on new genotypes or gene networks that are adaptable. A series of studies have reported that genes involved in local adaptation, such as anti-UV radiation (Yang et al.

这些近期的选择压力作用于可适应的新基因型或基因网络。一系列研究表明，参与局部适应的基因，如抗紫外线辐射（Yang等

2022

), pathogen antagonism (Klunk et al.

），病原体拮抗作用（Klunk 等人。

2022

), and dietary adaptation (Bersaglieri et al.

），以及饮食适应性（Bersaglieri 等人。

2004

2004年

; Kothapalli et al.

科塔帕利等。

2016

; Ye et al.

叶等。

2017

; Chen et al.

；陈等。

2022

) are under positive selection. If these genes are also involved in diseases due to genetic pleiotropic effects, then disease-associated genes could also be under positive selection. Whether this is the case in depression-associated genes remains unknown.

）受到正选择。如果这些基因由于遗传多效性效应也与疾病有关，那么与疾病相关的基因也可能受到正选择。抑郁症相关基因是否属于这种情况仍然未知。

Growing evidence has shown that depression has a polygenic genetic basis. With the rapid development of next generation sequencing technology, researchers have started to screen depression-associated genes at the whole-genomic level using genome-wide association studies (GWAS). Hundreds of genes have been identified to be associated with depression by using large cohorts from the UK Biobank, the Million Veteran Program, 23andMe, and FinnGen (Howard et al.

越来越多的证据表明，抑郁症具有多基因遗传基础。随着下一代测序技术的快速发展，研究人员已开始使用全基因组关联研究（GWAS）在全基因组水平上筛选与抑郁症相关的基因。通过利用来自英国生物银行、百万退伍军人计划、23andMe和FinnGen的大规模队列，研究人员已经识别出数百个与抑郁症相关的基因（Howard等）。

。

2018a

，

2019

; Wingo et al.

；温戈等。

2021

; Levey et al.

；Levey 等人。

2021

). Well-assembled and annotated genomes of multiple primate species are also available. These provide good resources for us to examine the selection pressures on the evolution of depression-associated genes in depth. Therefore, in this study, we investigated the positive selection on depression-associated genes retrieved from the GWAS studies mentioned above at two different levels, i.e., across the primate phylogeny (long timescale selection, i.e., millions of years) and in modern human populations (recent selection, about 100,000 years)..

）。目前已有多个人类灵长类物种的高质量组装和注释基因组可用。这些资源为我们深入研究抑郁症相关基因在进化过程中受到的选择压力提供了良好的基础。因此，在本研究中，我们在两个不同的层面上探讨了从上述GWAS研究中获取的抑郁症相关基因的正向选择，即跨越灵长类系统发育（长时间尺度选择，即数百万年）以及现代人类群体中的近期选择（约10万年）。

Materials and methods

材料与方法

Positive selection detection across the phylogeny

系统发育中的正选择检测

320 depression-associated genes at autosomes identified by GWAS were retrieved from literatures (Howard et al.

从文献中检索到由GWAS鉴定的320个与抑郁症相关的常染色体基因 (Howard等。

2018a

，

2019

; Wingo et al.

；温戈等。

2021

; Levey et al.

；Levey 等人

2021

) (Supplementary File

) （补充文件

). Ensembl IDs of human genes and corresponding orthologous genes of 21 primates across genomes were retrieved from the Ensembl database using BioMart (Cunningham et al.

). 从Ensembl数据库中使用BioMart检索了人类基因的Ensembl ID及对应于21种灵长类动物基因组的直系同源基因 (Cunningham等。

2022

). Only one-to-one orthologous genes with high confidence were analyzed. Coding genes and gff files for each species retrieved from the Ensembl database were used to extract corresponding coding sequences. The longest transcript of each gene was used for further analyses. Codon alignments were conducted using MAFFT implemented in T-coffee (Notredame et al.

仅分析了高可信度的一对一正交同源基因。从Ensembl数据库中获取每个物种的编码基因和gff文件，用于提取相应的编码序列。每个基因的最长转录本被用于进一步分析。密码子比对使用T-coffee（Notredame等）中实现的MAFFT进行。

。

2000

) with default parameters. An unrooted tree retrieved from the literature (Upham et al.

) 使用默认参数。从文献中检索到的无根树 (Upham 等。

2019

) was used for PAML analyses (Fig.

) 用于 PAML 分析（图。

）。

Fig. 1: Positive selection detection of depression-associated genes across the primate phylogeny under the branch-site model implemented in PAML.

图1：在PAML中实施的分支-位点模型下，跨灵长类系统发育的抑郁症相关基因的正选择检测。

Nine lineages were tested. The number of depression-associated genes under positive selection were given on each lineage.

测试了九个谱系。每个谱系中给出与抑郁相关的基因受到正选择的数量。

Full size image

全尺寸图像

The branch-site model in PAML was used to test positive selection across the phylogeny, which consider signals among both lineages and sites (Yang

PAML中的分支-位点模型用于检测整个系统发育中的正选择，该模型同时考虑了谱系和位点之间的信号 (Yang

1997

1997年

，

2007

2007年

). The value of

）。其价值

represents the ratio of nonsynonymous to synonymous substitutions. If the

表示非同义替换与同义替换的比率。如果

>>1, it means that the nonsynonymous mutations were favored by seletion. We detect positive selection on nine primate lineages (Fig.

>>1，这意味着非同义突变受到选择的青睐。我们在九个灵长类谱系中检测到正选择（图。

). To run the branch-site model in PAML, all branches within the target lineage were labeled as foreground branches. The M0 model was used to estimate initial branch lengths (fix_blength = 2). Alignment gaps and ambiguity characters were removed (Cleandata = 1). The modified Model A (model = 2, NSsites = 2) and the Model B (fix_omega = 1, omega = 1) were compared and a likelihood ratio test (LRT) was used to detect significance (Yang .

). 在PAML中运行分支-位点模型时，目标谱系中的所有分支都被标记为前景分支。使用M0模型估计初始分支长度（fix_blength = 2）。删除了比对空位和模糊字符（Cleandata = 1）。比较了修改后的Model A（model = 2, NSsites = 2）和Model B（fix_omega = 1, omega = 1），并使用似然比检验（LRT）检测显著性（Yang .

1997

1997年

，

2007

). Multiple test corrections were conducted using Bonferroni correction (Anisimova and Yang

). 使用Bonferroni校正进行了多重检验校正 (Anisimova 和 Yang

2007

2007年

; Gu and Xia

；顾和夏

2019

; Gu et al.

；顾等

2023

）。

Positive selection detection in modern human populations

现代人类群体中的正向选择检测

Haplotype-based methods (the integrated haplotype score (iHS) and the cross-population extended haplotype homozygosity (xpEHH)) which can limit demographic effects (Sabeti et al.

基于单倍型的方法（整合单倍型得分 (iHS) 和跨群体扩展单倍型纯合性 (xpEHH)），可以限制人口统计学效应 (Sabeti 等。

2002

; Voight et al.

; 沃伊特等

2006

; Nielsen et al.

尼尔森等。

2007

), as well as pairwise

)，以及成对的

开始

tests (Innan and Kim

测试（Innan 和 Kim）

2008

2008年

) were used to detect positive selection across the genome in different modern human populations, retrieved from the 1000 Genomes Project (ftp.1000genomes.ebi.ac.uk/vol1/ftp/release/20130502/). The iHS test can detect positively selected genes that have not been fixed in the population, and the xpEHH test can detect positively selected genes that are near/at fixation (Voight et al.

）被用于检测不同现代人类群体基因组中的正选择信号，数据来源于千人基因组计划（ftp.1000genomes.ebi.ac.uk/vol1/ftp/release/20130502/）。iHS测试可以检测在群体中尚未固定的正选择基因，而xpEHH测试可以检测接近/已固定的正选择基因（Voight等。

。

2006

2006年

; Sabeti et al.

；Sabeti 等人。

2007

2007年

). To further limit demographic effects, we focused on macro-populations, i.e. the African population, the East Asian population, the European population, and the South Asian population. We also removed recently admixed populations and geographically adjacent populations. Populations that we used were the same as the literature (Gu et al.

）。为了进一步限制人口统计学效应，我们聚焦于宏观人群，即非洲人群、东亚人群、欧洲人群和南亚人群。我们还剔除了近期混血的人群和地理上相邻的人群。我们使用的人群与文献（Gu等）中的一致。

。

2023

）。

The vcf files of autosomes retrieved from the 1000 Genomes Project were processed with PLINK (Purcell et al.

从1000基因组计划中获取的常染色体vcf文件使用PLINK进行了处理（Purcell等。

2007

; Chang et al.

；常等。

2015

) and VCFtools (Danecek et al.

) 和 VCFtools (Danecek 等。

2011

2011年

). The GRCh37/hg19 genome was used as the reference. SNPs with indels were not used. Since allele frequency and

）。GRCh37/hg19基因组被用作参考。带有插入缺失的SNP未被使用。由于等位基因频率和

开始

are highly correlated, we grouped

高度相关，我们将其分组

街霸

values in different allele frequency bins to define the

不同等位基因频率区间中的值来定义

街霸

threshold in each bin, and the top 5%

每个区间的阈值，以及前5%

开始时间

was used as the threshold.

被用作阈值。

街霸

and allele frequencies were calculated with VCFtools (Danecek et al.

并使用VCFtools计算等位基因频率（Danecek等。

2011

2011年

). The selscan software was used to calculate and standardize iHS and xpEHH scores for each SNP across the genome with default parameters (Szpiech and Hernandez

). 使用selscan软件通过默认参数计算并标准化全基因组中每个SNP的iHS和xpEHH得分（Szpiech和Hernandez

2014

). Only biallelic SNPs with minor allele frequency ≥ 0.05 in test populations were considered. The number of SNPs with

`). 仅考虑测试群体中次要等位基因频率≥0.05的双等位基因SNP。SNP的数量具有`

∣

iHS

∣

或

∣

xpEHH

∣

> 2 was counted in a 51-SNP window. When under positive selection, SNPs with large absolute scores of iHS or xpEHH tend to be clustered together (Voight et al.

> 2 被计数在一个 51-SNP 窗口中。当处于正选择时，iHS 或 xpEHH 绝对分数较大的 SNP 往往会聚集在一起（Voight 等）。

2006

2006年

). Only SNPs with

). 仅包含SNPs与

∣

iHS

∣

或

∣

xpEHH

∣

竖线符号在数学和编程中有多种含义，具体取决于上下文。以下是几种常见的解释：1. **绝对值**：在数学中，竖线符号通常用来表示绝对值。例如，`|x|` 表示变量 `x` 的绝对值，即不考虑其正负号的值。2. **集合的基数**：在集合论中，竖线可以表示集合的基数（即集合中元素的数量）。例如，`|A|` 表示集合 `A` 中元素的个数。3. **条件概率**：在概率论中，竖线用于表示条件概率。例如，`P(A|B)` 表示在事件 `B` 发生的条件下事件 `A` 发生的概率。4. **逻辑或运算符**：在某些编程语言中，双竖线 `||` 用作逻辑或运算符，而单竖线 `|` 可能表示按位或运算。5. **范数**：在线性代数中，竖线可以表示向量或矩阵的范数。例如，`|v|` 可以表示向量 `v` 的长度或范数。6. **分割符号**：在某些情况下，竖线可以用作分隔符来区分不同的元素或选项。由于竖线符号的多义性，具体的含义需要结合上下文来确定。

> 2 in a top 1% 51-SNP window, as well as with high

> 2 在前 1% 的 51-SNP 窗口中，以及高

街

values were considered under positive selection. Given the use of genome-wide empirical distributions for standardization, no formal significance testing was conducted when employing these haplotype-based methods, as noted in the literature (Voight et al.

这些值被认为处于正选择之下。鉴于使用了全基因组经验分布进行标准化，在应用这些基于单倍型的方法时，如文献所述（Voight等），并未进行正式的显著性检验。

2006

2006年

). We focused on SNPs located in exons in this study. After identifying positively selected genes across the genome in different populations, we compared this gene list with depression-associated genes we have retrieved to identify which depression-associated genes were under positive selection. GO annotations of positively selected genes were conducted with DAVID (Huang et al.

）。本研究重点关注位于外显子中的SNPs。在鉴定不同群体中全基因组的正选择基因后，我们将其与已检索到的抑郁相关基因列表进行比较，以确定哪些抑郁相关基因处于正选择之下。正选择基因的GO注释通过DAVID进行（Huang等，

。

2009

2009年

; Sherman et al.

；谢尔曼等。

2022

）。

Statistical analyses at the genomic level

全基因组水平的统计分析

Fisher tests were conducted for pairwise comparisons between humans and other primates to determine whether the proportion of positively selected depression-associated genes was significantly different. To determine whether the proportion of positively selected depression-associated genes was significantly larger than the proportion of positively selected genes at the genomic level (at the autosomal level) in the target branch, we randomly selected 320 genes (the same number as depression-associated genes we tested) across the genome using homologous genes retrieved for PAML analyses each time, and recorded how many of them were under positive selection in that branch.

进行了费舍尔检验以进行人类与其他灵长类动物之间的成对比较，来确定正选择相关的抑郁症基因比例是否存在显著差异。为了确定在目标分支中，正选择相关的抑郁症基因比例是否显著高于基因组水平（常染色体水平）的正选择基因比例，我们每次随机选取了320个基因（与我们测试的抑郁症相关基因数量相同），这些基因来自全基因组范围，并使用为PAML分析检索到的同源基因，记录其中在该分支中有多少基因受到正选择的影响。

We repeated these steps 100,000 times for each branch and plotted the density distribution. Then, we checked whether the actual number of positively selected depression-associated genes was extremely high (located outside the 5% tails of the distribution)..

我们对每个分支重复这些步骤10万次并绘制了密度分布图。然后，我们检查了实际的正选择抑郁症相关基因的数量是否极高（位于分布的5%尾部之外）。

To determine whether the proportion of positively selected depression-associated genes in the target population was significantly larger than the proportion of positively selected genes at the genomic level (at the autosomal level) in that population, we randomly selected 320 genes (the same number as depression-associated genes we tested) across the genome each time and recorded how many of them were under positive selection in that population.

为了确定目标人群中正向选择的抑郁症相关基因的比例是否显著大于该人群基因组水平（常染色体水平）上正向选择基因的比例，我们每次随机选择320个基因（与我们测试的抑郁症相关基因数量相同），并记录其中有多少基因在该人群中受到正向选择。

We repeated these steps 100,000 times for each population and plotted the density distribution. Then we checked whether the actual number of positively selected depression-associated genes was extremely high (located outside the 5% tails of the distribution)..

我们对每个群体重复这些步骤10万次并绘制了密度分布图。然后我们检查了实际的正选择抑郁症相关基因的数量是否极高（位于分布的5%尾部之外）。

Gene Ontology annotations

基因本体注释

Gene Ontology biological process terms were retrieved from AmiGO (

从AmiGO检索到了基因本体生物学过程术语（

https://amigo.geneontology.org/amigo/

) (Ashburner et al.

) (Ashburner 等人。

2000

; Carbon et al.

；Carbon 等人。

2009

; Aleksander et al.

; 亚历山大等

2023

）。

Expression quantitative trait loci (eQTLs) for positively selected variants

正向选择变异的表达数量性状位点 (eQTL)

To see whether positively selected SNPs function as eQTLs, the GTExPortal V8 (

为了查看正向选择的SNPs是否作为eQTLs起作用，GTExPortal V8 (

https://www.gtexportal.org/home/

) was used to acquire corresponding information (Ardlie et al.

）被用于获取相应信息（Ardlie等，

2015

2015年

). The m-value (Posterior probability from MetaSoft) was used to measure the eQTL effects in multiple tissues (Han and Eskin

). 使用m值（来自MetaSoft的后验概率）来衡量多组织中的eQTL效应 (Han and Eskin

2011

2011年

，

2012

2012年

). If m > 0.9, it means that the variant does have an eQTL effect in the tissue.

). 如果 m > 0.9，则表示该变异在该组织中确实具有 eQTL 效应。

Results

结果

Depression-associated genes under positive selection across the primate phylogeny

在整个灵长类系统发育过程中受到正选择的抑郁症相关基因

Among the 320 depression-associated genes we tested, seven genes were under positive selection in the human lineage (Table

在我们测试的320个与抑郁症相关的基因中，有七个基因在人类谱系中受到正选择（表

, Fig.

，图。

), including the immune response-related gene STAU1 (Pang et al.

)，包括与免疫反应相关的基因 STAU1（Pang 等人。

2021

), the neurodegeneration-related gene PSEN2 (Fedeli et al.

），与神经退行性疾病相关的基因 PSEN2（Fedeli 等。

2019

), the neurological-related gene ANKK1 (Hoenicka et al.

)，与神经相关的基因ANKK1（Hoenicka等。

2010

2010年

), the electron transfer flavoprotein dehydrogenase ETFDH (Zhang and Zhao

), 电子转移黄素蛋白脱氢酶 ETFDH (Zhang 和 Zhao

2022

), zinc fingers and homeoboxes 3 ZHX3, the neural development-related gene PCDH9 (Chen et al.

)，锌指和同源框3 ZHX3，神经发育相关基因PCDH9（Chen等。

2024

), and immune-related gene LYRM4 (Wang et al.

），以及免疫相关基因LYRM4（Wang等。

2023

）。

Table 1 Depression-associated genes under positive selection in the human lineage.

表1 人类谱系中正向选择的抑郁症相关基因。

Full size table

全尺寸表格

Compared to the human lineage, more depression-associated genes were identified under positive selection in other lineages. For example, 25 depression-associated genes were under positive selection in branch 2, which is the sister lineage to human beings, including

与其他谱系相比，人类谱系中受到正选择的抑郁症相关基因较少。例如，在分支2中有25个抑郁症相关基因受到正选择，该分支是与人类谱系最近的姐妹谱系，包括

Pan troglodytes

黑猩猩

and

和

Pan paniscus

倭黑猩猩

. Twenty-nine depression-associated genes were under positive selection in branch 3, the ancestral lineage leading to human beings. Moreover, there were 57 depression-associated genes under positive selection in branch 4, 35 depression-associated genes under positive selection in branch 5, 96 depression-associated genes under positive selection in branch 6, 86 depression-associated genes under positive selection in branch 7, 25 depression-associated genes under positive selection in branch 8, and 18 depression-associated genes under positive selection in branch 9 (Fig.

在分支3中，即通往人类的祖先谱系中，有29个与抑郁症相关的基因受到正选择。此外，在分支4中有57个与抑郁症相关的基因受到正选择，在分支5中有35个与抑郁症相关的基因受到正选择，在分支6中有96个与抑郁症相关的基因受到正选择，在分支7中有86个与抑郁症相关的基因受到正选择，在分支8中有25个与抑郁症相关的基因受到正选择，在分支9中有18个与抑郁症相关的基因受到正选择（图。

。

）。

We further tested whether the proportion of positively selected depression-associated genes was significantly larger than the proportion of positively selected genes at the whole genomic level. We performed statistical significance tests in all target lineages and did not find any significantly large result.

我们进一步测试了正选择的抑郁症相关基因的比例是否显著大于全基因组水平上正选择基因的比例。我们在所有目标谱系中进行了统计显著性检验，但没有发现任何显著较大的结果。

In most cases, there were no significant differences, and the proportion of positively selected depression-associated genes was even significantly less than the proportion of positively selected genes at the genomic level in certain lineages (branch 5, branch 6, branch 7 and branch 8) (Fig. .

在大多数情况下，没有显著差异，甚至在某些谱系（分支5、分支6、分支7和分支8）中，正选择的抑郁症相关基因的比例显著低于基因组水平正选择基因的比例（图。

）。

Fig. 2: Statistical analyses of depression-associated genes under positive selection in different primate lineages.

图2：不同灵长类谱系中与抑郁相关的基因在正选择下的统计分析。

Statistical analyses showed that the number of positively selected depression-associated genes in non-human primate lineages were significantly larger than the one in the human lineage.

统计分析显示，非人灵长类谱系中正向选择的抑郁症相关基因数量显著多于人类谱系中的数量。

The proportion of positively selected depression-associated genes was not significantly larger than the proportion of positively selected genes at the genomic level in target primate lineages. * represents

目标灵长类谱系中正向选择的抑郁症相关基因的比例并不显著高于基因组水平上正向选择基因的比例。* 代表

< 0.05; ** represents

小于0.05；** 表示

< 0.01.

< 0.01。

Full size image

全尺寸图像

Depression-associated genes under positive selection in modern human populations

现代人群中与抑郁症相关的基因受到正选择

Genome-wide positive selection detection identified 215 genes under positive selection in the African population, 592 genes under positive selection in the East Asian population, 632 genes under positive selection in the European population, and 567 genes under positive selection in the South Asian population.

全基因组正选择检测发现，非洲人群中有215个基因受到正选择，东亚人群中有592个基因受到正选择，欧洲人群中有632个基因受到正选择，南亚人群中有567个基因受到正选择。

We further identified 46 depression-associated genes under positive selection in total. Among them, nine depression-associated genes were identified under positive selection by both the iHS test and the .

我们总共进一步鉴定了46个在正选择下的抑郁相关基因。其中，有9个抑郁相关基因被iHS检验和同时鉴定为在正选择之下。

开始时间

test, and 45 depression-associated genes were identified under positive selection by both the xpEHH test and the

测试，通过xpEHH测试和

开始时间

test (Table

测试（表

, Supplementary File

，补充文件

). Depression-associated genes under positive selection exhibited population-specific patterns. There were eight genes (HLA-DQA1, HLA-DQB1, MGAT4C, ZNF536, SIM1, METTL9, MYRF, PSORS1C1) under positive selection in the African population, five genes (BEND4, CDH13, SOX6, POGZ, PSMB4) under positive selection in the European population, 17 genes (SDK1, CCDC92, DENND1A, USP3, C22orf26, BEND4, ASXL3, TENM2, BSN, ZNF35, MGAT4C, CTNND1, FNIP2, NRD1, INPP4B, C7orf72, FHIT) under positive selection in the East Asian population, and 25 genes (FADS1, FADS2, HLA-DQA1, HLA-DQB1, FAM120A, DENND1A, C22orf26, BEND4, FAM120AOS, ASCC3, LPIN3, POGZ, EMILIN3, CDH9, SGIP1, ZNF660, NICN1, CCDC36, CCDC71, TCAIM, MGAT4C, ZNF445, ZNF197, ZKSCAN7, PHF2) under positive selection in the South Asian population (Table .

与抑郁症相关的基因在正选择下表现出人群特异性模式。非洲人群中有八个基因（HLA-DQA1、HLA-DQB1、MGAT4C、ZNF536、SIM1、METTL9、MYRF、PSORS1C1）受到正选择，欧洲人群中有五个基因（BEND4、CDH13、SOX6、POGZ、PSMB4）受到正选择，东亚人群中有17个基因（SDK1、CCDC92、DENND1A、USP3、C22orf26、BEND4、ASXL3、TENM2、BSN、ZNF35、MGAT4C、CTNND1、FNIP2、NRD1、INPP4B、C7orf72、FHIT）受到正选择，南亚人群中有25个基因（FADS1、FADS2、HLA-DQA1、HLA-DQB1、FAM120A、DENND1A、C22orf26、BEND4、FAM120AOS、ASCC3、LPIN3、POGZ、EMILIN3、CDH9、SGIP1、ZNF660、NICN1、CCDC36、CCDC71、TCAIM、MGAT4C、ZNF445、ZNF197、ZKSCAN7、PHF2）受到正选择（表。

, Supplementary File

，补充文件

). FADS1 and FADS2 which are related to dietary adaptation have been previously reported to be under positive selection (Kothapalli et al.

). 与饮食适应相关的FADS1和FADS2之前被报道受到正选择（Kothapalli等。

2016

; Ye et al.

叶等。

2017

2017年

; Chen et al.

；陈等。

2022

）。

Table 2 Depression-associated genes under positive selection in different human populations.

表2 不同人群中与抑郁症相关的正向选择基因。

Full size table

全尺寸表格

Notably, the proportions of depression-associated genes under positive selection in the African population (8 out of 320) (

值得注意的是，非洲人群中与抑郁症相关的基因在正选择下的比例（320个中有8个）（

< 0.05), in the East Asian population (17 out of 320) (

<0.05)，在东亚人群中（320人中有17人）（

< 0.05), and in the South Asian population (25 out of 320) (

<0.05），在南亚人群中（320人中有25人）（

< 0.01) were significantly larger than the proportions of positively selected genes at the genomic level in the corresponding populations (Fig.

<0.01) 显著大于相应群体中基因组水平上正选择基因的比例 (图。

）。

Fig. 3: Recent selection plays important roles on the adaptive evolution of depression-associated genes in modern human populations.

图3：近期选择在现代人类群体中抑郁症相关基因的适应性进化中发挥了重要作用。

The number of positively selected depression-associated genes and the number of positively selected genes at the genomic level in each population.

每个群体中正向选择的抑郁症相关基因的数量和基因组水平上正向选择的基因数量。

Proportions of positively selected variants located in different regions (5’ UTR, 3’ UTR, coding region and non-coding exons).

位于不同区域（5' UTR、3' UTR、编码区和非编码外显子）的正向选择变异的比例。

The proportion of positively selected depression-associated genes in the African population, the East Asian population and the South Asian population was significantly larger than the proportion of positively selected genes at the corresponding genomic level.

非洲人群、东亚人群和南亚人群中正向选择的抑郁症相关基因的比例显著高于相应基因组水平上正向选择基因的比例。

left: xpEHH plot of two positively selected variants that happened to be depression-associated variants in the South Asian population compared to the European population. middle: the distribution of

左图：xpEHH 图显示了两个在南亚人群中与抑郁症相关的正向选择变异，与欧洲人群相比。中间：分布情况

街

values across the genome between the South Asian population and the European population. The

全基因组范围内南亚人口与欧洲人口之间的值。

开始

value of two positively selected variants was located at the top 5% region of the corresponding distribution (

两个正向选择变异的值位于相应分布的前 5% 区域（

< 0.05). right: allele frequencies of two positively selected variants in the European population and in the South Asian population.

<0.05)。右图：欧洲人群和南亚人群中两个正向选择变异的等位基因频率。

Full size image

全尺寸图像

Expression quantitative trait loci (eQTLs) for positively selected variants

正向选择变异的表达数量性状位点 (eQTL)

The eQTL effects of each positively selected variant at UTR regions were obtained from the GTExPortal V8. Results showed that most positively selected variants have eQTL effects across multiple tissues, and many of which were in non-brain tissues (Fig.

通过GTExPortal V8获得了每个在UTR区域受到正选择的变异的eQTL效应。结果表明，大多数受到正选择的变异在多种组织中具有eQTL效应，其中许多位于非脑组织（图。

）。

Fig. 4: The eQTL effects of each positively selected variant in multiple tissues.

图4：每个正向选择变异在多种组织中的eQTL效应。

The m-value was used to measure the eQTL effects in multiple tissues (Han and Eskin

m值被用于测量多组织中的eQTL效应（Han和Eskin

2011

2011年

，

2012

). If m > 0.9, it means that the variant does have an eQTL effect in the tissue. red, m > 0.9; blue, m ≤ 0.9. Only variants with available information in the GTEx database were shown.

). 如果 m > 0.9，表示该变异在组织中确实具有 eQTL 效应。红色：m > 0.9；蓝色：m ≤ 0.9。仅显示 GTEx 数据库中具有可用信息的变异。

Full size image

全尺寸图像

Discussion

讨论

We identified seven depression-associated genes under positive selection in the human lineage. Non-human primates showed more depression-associated genes under positive selection than humans. This phenomenon is consistent with findings indicating that humans have fewer genes under positive selection compared to non-human primates (Gibbs et al.

我们在人类谱系中鉴定了七个受到正选择的抑郁症相关基因。非人灵长类动物显示出比人类更多的受到正选择的抑郁症相关基因。这一现象与表明人类相较于非人灵长类动物拥有更少受正选择基因的研究结果一致（Gibbs等）。

。

2007

; Bakewell et al.

; 贝克韦尔等

2007

). There are several possible explanations for our findings. Recent studies indicate that brain evolution occurred not only in humans but also in non-human primates, such as the Simiiformes ancestor, which displayed significant morphological changes, including rapid brain expansion (Hu et al.

). 对于我们的研究结果，有几种可能的解释。最近的研究表明，大脑进化不仅发生在人类身上，也发生在非人类灵长类动物身上，例如猿猴祖先，它们表现出显著的形态变化，包括大脑的快速扩张 (Hu等。

2024

). Primate brain evolution has been a continuous process marked by the expansion of the neocortex and the development of higher cognitive functions (Zhuang et al.

）。灵长类大脑的进化是一个持续的过程，以新皮层的扩张和高级认知功能的发展为标志（Zhuang等。

2023

; Hu et al.

胡等。

2024

). Another explanation could be gene pleiotropy. Many positively selected genes in non-human primates are involved in functions beyond brain development, such as reproduction, metabolism, dietary adaptation, and immunity (Supplementary

). 另一种解释可能是基因多效性。许多在非人灵长类动物中受到正选择的基因除了参与大脑发育外，还涉及繁殖、代谢、饮食适应和免疫等功能（补充材料）。

). Similar patterns have been observed in cancer-associated (Lou et al.

). 在癌症相关的研究中也观察到了类似的模式（Lou等。

2014

2014年

; Vicens and Posada

；维森斯和波萨达

2018

; Gu et al.

；顾等

2023

) and Alzheimer’s disease-associated genes (Vamathevan et al.

）和阿尔茨海默病相关基因（Vamathevan 等。

2008

2008年

). Additionally, environmental and societal pressures differ between humans and non-human primates, leading to distinct selective pressures on the same gene functions. For example, genes related to emotional regulation may promote social bonding in non-human primates (Platt et al.

此外，人类和非人灵长类动物面临的环境和社会压力不同，导致对相同基因功能的选择压力各异。例如，与情绪调节相关的基因可能在非人灵长类动物中促进社会联结（Platt等）。

2016

), whereas excessive emotional sensitivity may lead to stress and negative effects which could be detrimental in humans (Dosari et al.

），而过度的情绪敏感可能会导致压力和负面影响，这对人类来说可能是有害的（Dosari 等。

2023

), making such traits less advantageous.

)，使得这些特性不那么有利。

The seven positively selected depression-associated genes we identified in the human lineage are involved in brain development (PSEN2, ANKK1, PCDH9) and immunity (STAU1 and LYRM4), as highlighted in our results. It has been demonstrated that PSEN2 knock-in mice exhibit severe depressive behavior (Yoo et al.

我们在人类谱系中鉴定出的七个正向选择的抑郁症相关基因参与了大脑发育（PSEN2、ANKK1、PCDH9）和免疫（STAU1 和 LYRM4），正如我们的结果所强调的那样。研究表明，PSEN2 敲入小鼠表现出严重的抑郁行为（Yoo 等）。

。

2024

), and PCDH9 and ANKK1 have also been reported as risk genes for depression (Roetker et al.

），PCDH9和ANKK1也被报道为抑郁症的风险基因（Roetker等。

2012

2012年

; Xiao et al.

肖等。

2018

). The positive selection of these genes in the human lineage may attributed to their pleiotropic effects. For example, brain-related genes have long been associated with cognitive evolution in humans (Zhuang et al.

）。这些基因在人类谱系中的正选择可能归因于它们的多效性效应。例如，脑相关基因长期以来一直与人类的认知进化有关（Zhuang等。

2023

; Hu et al.

胡等。

2024

), while immunity likely played a role in responding to new environments and pathogens during human evolution (Benton et al.

），而免疫可能在人类进化过程中对新环境和病原体的反应中发挥了作用（Benton 等。

2021

）。

Notably, among the 46 depression-associated genes under positive selection in modern human populations, we identified two genes harboring depression-associated SNPs that are also under positive selection (Fig.

值得注意的是，在现代人群中受到正选择的46个抑郁相关基因中，我们发现了两个携带抑郁相关SNPs且同样受到正选择的基因（图。

). One is located in the gene FADS1. The odds ratio (OR) for allele T on rs174546 of FADS1 was significantly greater than 1 (OR = 1.015,

). 其中一个位于FADS1基因中。FADS1基因上rs174546位点的T等位基因的比值比（OR）显著大于1（OR = 1.015，

= 0.000856) (Howard et al.

= 0.000856) （Howard 等人

2018b

), indicating an increased risk of depression. Despite this, the locus is under positive selection, suggesting it may provide an adaptive advantage in certain environmental or evolutionary contexts. FADS1 is known for its role in dietary adaptation in South Asian population (Kothapalli et al.

），这表明抑郁风险增加。尽管如此，该位点处于正向选择中，表明它可能在某些环境或进化背景下提供适应性优势。FADS1 因其在南亚人群饮食适应中的作用而闻名（Kothapalli 等）。

2016

; Ye et al.

叶等。

2017

; Chen et al.

；陈等人。

2022

), supporting the biosynthesis of long-chain polyunsaturated fatty acids, which are crucial for individuals on plant-based diets. This gene’s pleiotropic trade-off could explain the positive selection of this depression-associated locus in South Asians. Another positively selected depression-associated SNP is located in the gene ZNF445, which is involved in post-fertilization methylation maintenance and imprinting disorders (Takahashi et al.

），支持长链多不饱和脂肪酸的生物合成，这对于遵循植物性饮食的人来说至关重要。该基因的多效性权衡可以解释南亚人群中这个与抑郁症相关的位点的正向选择。另一个正向选择的抑郁症相关SNP位于基因ZNF445中，该基因参与受精后甲基化维持和印记疾病（Takahashi等，）。

。

2019

). Unlike the SNP in FADS1, the SNP in ZNF445 has an OR for allele T on rs2372688 of 0.98 (

). 与FADS1中的SNP不同，ZNF445中的SNP对rs2372688上等位基因T的OR值为0.98 (

= 0.000006758) (Howard et al.

= 0.000006758) （Howard 等人

2018b

2018年版

), suggesting a protective effect against depression. Carriers of this variant may be less prone to depression and better adapted to environmental or social conditions, enhancing their survival and reproductive success. Further research is needed to explore the detailed function of this variant. Together, these two variants offer valuable complementary evidence that disease (depression)-associated loci can undergo positive selection in specific populations..

），这暗示了其对抑郁症的保护作用。携带该变异的个体可能较不易患抑郁症，并且更能适应环境或社会条件，从而提高他们的生存和繁殖成功率。需要进一步研究来探索该变异的详细功能。综上所述，这两种变异提供了宝贵的互补证据，表明与疾病（抑郁症）相关的基因座在特定人群中可能会经历正向选择。

For the additional 44 depression-associated genes detected under positive selection in different human populations, although the loci subjected to positive selection are not directly linked to depression but rather to other loci within the genes, the positive selection of these genes may have led to their wider prevalence across human populations over time.

对于在不同人群中检测到的另外44个受正选择影响的抑郁症相关基因，尽管受到正选择的位点并非直接与抑郁症相关，而是与基因内的其他位点相关，但这些基因的正选择可能导致它们随着时间的推移在人群中更广泛地传播。

This increased frequency could provide more opportunities for the associated depression-related variants to exert their effects, whether by indirectly promoting or inhibiting depression. Most of these genes are not only involved in neuron development, but also play roles in immune response, metabolism, dietary excess, and reproduction (e.g., spermatogenesis) (see Table .

这种频率的增加可能会为相关的抑郁相关变异提供更多的机会来发挥其作用，无论是通过间接促进还是抑制抑郁。这些基因大多数不仅参与神经元发育，还在免疫反应、代谢、饮食过剩和生殖（例如，精子发生）中发挥作用（见表。

). As we know, the environment has changed a lot after migration out of Africa in the last 100,000 years, such as exposure to diverse pathogens, diversified food resources, and social culture (Benton et al.

).众所周知，在过去十万年间人类走出非洲后环境发生了很大变化，比如暴露于多种病原体、食物资源多样化以及社会文化（Benton等。

2021

). In fact, many of the depression-associated genes that underwent positive selection in both African and South Asian populations are immune-related, such as HLA-DQA1, HLA-DQB1, and MGAT4C. Given that Africa and South Asia are located in tropical regions with greater diversity of pathogens and parasites compared to other populations, these genes could be under positive selection due to their association with immune functions.

事实上，许多在非洲和南亚人群中经历正选择的与抑郁症相关的基因都与免疫有关，例如HLA-DQA1、HLA-DQB1和MGAT4C。鉴于非洲和南亚位于热带地区，与其他人群相比，其病原体和寄生虫的多样性更高，这些基因可能由于与免疫功能的关联而受到正选择。

Additionally, some depression-associated genes in the South Asian population are linked to diet and metabolism, such as FADS1, FADS2, LPIN3, and SGIP1. As we mentioned above, FADS1 and FADS2 are well-known for their roles in dietary adaptation in the South Asian population (Kothapalli et al. .

此外，南亚人群中一些与抑郁症相关的基因与饮食和代谢有关，例如 FADS1、FADS2、LPIN3 和 SGIP1。正如我们上面提到的，FADS1 和 FADS2 在南亚人群的饮食适应中发挥了重要作用 (Kothapalli 等)。

2016

; Ye et al.

叶等。

2017

; Chen et al.

；陈等。

2022

). These depression-associated genes may therefore under positive selection in modern human populations due to their pleiotropic effects.

因此，这些与抑郁症相关的基因可能由于其多效性效应而在现代人类群体中受到正向选择。

Our results also showed that most positively selected variants were located in UTR regions and non-coding exons. In recent years, there has been increasing recognition that not all exons encode proteins (Aspden et al.

我们的结果还表明，大多数正向选择的变异位于UTR区域和非编码外显子中。近年来，人们越来越认识到，并非所有外显子都编码蛋白质（Aspden等。

2023

). For instance, a study has demonstrated that multiple non-coding exons within the brain-derived neurotrophic factor (BDNF) can produce differently spliced transcripts, potentially influencing psychiatric diseases like depression (Begni et al.

）。例如，一项研究已经证明，脑源性神经营养因子（BDNF）中的多个非编码外显子可以产生不同剪接的转录本，可能影响抑郁症等精神疾病（Begni等。

2017

). Currently, research on non-coding exons in relation to depression is limited. Therefore, the positively selected sites in non-coding exons we have identified here are good candidates for further study. Regarding the UTR regions, the 5’-UTR harbors various regulatory elements, including sites for ribosome recruitment, binding sites for microRNAs, and structural components crucial for governing mRNA stability, pre-mRNA splicing, and the initiation of translation (Ryczek et al.

）。目前，关于非编码外显子与抑郁症相关的研究较为有限。因此，我们在此鉴定出的非编码外显子中的正选择位点是进一步研究的良好候选对象。关于UTR区域，5’-UTR包含多种调控元件，包括核糖体招募位点、microRNA结合位点以及对mRNA稳定性、前体mRNA剪接和翻译起始至关重要的结构组分（Ryczek等。

。

2023

). Consequently, the 5’-UTR plays a crucial role in gene expression control. While their link to depression remains relatively sparse, one study has proposed that epigenetic methylation in the 5’-UTR region could influence glucocorticoid receptor splicing, which is implicated in depression (Turner et al.

). 因此，5’-UTR在基因表达调控中起着关键作用。尽管它们与抑郁症的联系仍然相对较少，但一项研究提出，5’-UTR区域的表观遗传甲基化可能影响糖皮质激素受体的剪接，这与抑郁症有关（Turner等。

。

2010

2010年

). For 3’-UTR regions, they are renowned for providing binding sites for small RNAs, thus regulating gene expression at the post-transcriptional level, which significantly contributes to controlling behaviors like social interactions and anxiety, relevant to depression (Narayanan and Schratt

). 对于3'-UTR区域，它们因提供小RNA的结合位点而闻名，从而在转录后水平调控基因表达，这对控制与抑郁相关的行为（如社交互动和焦虑）有重要贡献（Narayanan和Schratt）。

2020

). This has been underscored by various studies, such as alternative splicing of the serotonin-1A receptor (Le François et al.

). 这一点已通过各种研究得到了强调，例如血清素-1A受体的可变剪接（Le François等。

2018

) and the regulation of VGF protein expression, a precursor of secreted neuropeptides (Lin et al.

）以及VGF蛋白表达的调节，VGF是分泌型神经肽的前体（Lin等。

2021

). Therefore, the positively selected SNPs identified in UTR regions and non-coding exons in our study represent promising candidates for understanding their potential roles in depression. Besides, most of the positively selected depression-associated genes had eQTL effects in multiple tissues, especially in non-brain tissues, confirming again their pleiotropic effects..

).因此，我们在UTR区域和非编码外显子中鉴定出的正选择SNPs代表了理解它们在抑郁症中潜在作用的有希望的候选者。此外，大多数正选择的抑郁症相关基因在多种组织中具有eQTL效应，尤其是在非脑组织中，再次证实了它们的多效性作用。

We further revealed that the proportion of positively selected depression-associated genes was so high that it was even significantly larger than the proportions of positively selected genes at the genomic level in several modern human populations, i.e., in the African population, the East Asian population and the South Asian population, but not in the European population.

我们进一步揭示了正选择抑郁症相关基因的比例如此之高，以至于在几个现代人类群体中，它甚至显著大于基因组水平上正选择基因的比例，例如在非洲人群、东亚人群和南亚人群中，但在欧洲人群中则不然。

As shown in Table .

如表所示。

, many positively selected genes in non-European populations are linked to immunity, neurodevelopment, metabolism, dietary adaptation, and reproduction. The disparities between non-European and European populations may stem from several factors. For example, diets in Africa, South Asia, and East Asia are more plant-based than in Europe.

，非欧洲人群中许多正向选择的基因与免疫、神经发育、代谢、饮食适应和生殖有关。非欧洲人群和欧洲人群之间的差异可能源于几个因素。例如，非洲、南亚和东亚的饮食比欧洲更以植物为主。

Social structures in these regions are also more conservative and community-oriented. And non-European populations face greater social competition due to economic growth, population density, and higher biodiversity. However, as mentioned above, most of the positively selected loci are not directly associated with depression, but rather are other loci within depression-associated genes.

这些地区的社会结构也更加保守和以社区为导向。非欧洲人口由于经济增长、人口密度和更高的生物多样性而面临更大的社会竞争。然而，如上所述，大多数正向选择的基因位点并不直接与抑郁症相关，而是抑郁症相关基因中的其他位点。

Therefore, we cannot conclude whether depression is adaptive in different populations at this stage. What we can say here is that these depression-associated genes can experience different selective pressures across populations, and these pressures are closely linked to their pleiotropic effects..

因此，我们目前无法断定抑郁症在不同人群中是否具有适应性。我们能说的是，这些与抑郁症相关的基因在不同人群中会经历不同的选择压力，而这些压力与其多效性效应密切相关。

It is important to note that the depression-associated genes we tested were retrieved from individuals of European descent (Howard et al.

需要注意的是，我们测试的与抑郁症相关的基因是从欧洲裔个体中获取的（Howard 等人。

2018a

，

2019

; Wingo et al.

；温戈等。

2021

; Levey et al.

；Levey 等人。

2021

). However, GWAS data from non-European populations are currently limited, which restricts our ability to conduct a more comprehensive analysis. Future research, when relevant data becomes available, could provide further insights. Despite these limitations, our current study provides a valuable resource and logical framework for future analyses.

然而，目前非欧洲人群的GWAS数据有限，这限制了我们进行更全面分析的能力。未来研究在相关数据可用时，可能会提供更多的见解。尽管存在这些局限性，我们目前的研究为未来的分析提供了宝贵的资源和逻辑框架。

Moreover, our research highlights that depression-associated genes, or more broadly, disease-associated genes, can be subject to different selective pressures in different populations, and even undergo positive selection. For example, one of the risk locus in FADS1 we identified, significantly associated with depression, was under positive selection in a specific population.

此外，我们的研究强调，与抑郁症相关的基因，或者更广泛地说，与疾病相关的基因，在不同人群中可能会受到不同的选择压力，甚至可能经历正向选择。例如，我们在FADS1中发现的一个风险位点，与抑郁症显著相关，在特定人群中经历了正向选择。

This suggests that in precision medicine research, it is important to take into account the specific factor of how genes exert their functions in particular populations..

这表明在精准医学研究中，必须考虑到基因在特定人群中发挥作用的具体因素。

Data availability

数据可用性

All data generated or analyzed during this study are included in this published article and its supplementary information files. Phased genetic data of the 1000 Genomes Project of modern human populations were retrieved from

本研究期间生成或分析的所有数据均包含在本文及其补充信息文件中。现代人类群体的1000基因组计划的阶段性遗传数据取自

ftp.1000genomes.ebi.ac.uk/vol1/ftp/release/20130502/

。

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Acknowledgements

致谢

This work was supported by Fundamental Research Funds for the Central Universities (20lgpy109) to LG, and by the Scientific Research Team Project of the College of Life Sciences, Beijing Normal University in 2024 to CX. Data computation was supported by National Supercomputer Center in Guangzhou, China..

这项工作得到了中央高校基本科研业务费（20lgpy109）对LG的支持，以及2024年北京师范大学生命科学学院科研团队项目对CX的支持。数据计算得到了中国广州国家超级计算中心的支持。

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Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China

中国广东省广州市中山大学肿瘤中心，邮编510060

Shiyu Yang

杨世宇

The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510180, China

中国广东省广州市，广州医科大学附属脑科医院，邮编510180

Shiyu Yang

杨世宇

State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China

中国广东省广州市中山大学生命科学学院生物控制国家重点实验室，邮编510275

Chenqing Zheng & Langyu Gu

郑晨清 & 顾朗宇

Ministry of Education Key Laboratory for Biodiversity and Ecological Engineering, College of Life Sciences, Beijing Normal University, Beijing, 100875, China

教育部生物多样性和生态工程重点实验室，北京师范大学生命科学学院，北京，100875，中国

Canwei Xia

夏灿伟

Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China

中国广东省广州市中山大学附属第一医院病理科，邮编510080

Jihui Kang

康继辉

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SY and LG designed the study. SY and LG conducted positive selection detection in modern human populations. SY, CZ and LG conducted positive selection detection across the phylogeny. SY, CX and LG conducted statistical analyses. JK conducted data curation. SY and LG wrote the manuscript and all authors commented on it..

SY和LG设计了这项研究。SY和LG在现代人群中进行了正选择检测。SY、CZ和LG在整个系统发育过程中进行了正选择检测。SY、CX和LG进行了统计分析。JK进行了数据管理。SY和LG撰写了手稿，所有作者都对其进行了评论。

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Langyu Gu

谷浪宇

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Yang, S., Zheng, C., Xia, C.