Rao Shuquan, Baranova Ancha, Yao Yao, Wang Jun, Zhang Fuquan
Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
School of Systems Biology, George Mason University, Manassas, Virginia, USA.
Neuropsychobiology. 2022;81(6):484-496. doi: 10.1159/000525411. Epub 2022 Jun 28.
Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) commonly co-occur; both traits exert an influence on intelligence scores. Genetic relationships between these three traits are far from being clear.
The summary results of genome-wide association studies of ADHD (20,183 cases and 35,191 controls), ASD (18,381 cases and 27,969 controls), and intelligence (269,867 participants) were used for the analyses. Local genetic correlation analysis and polygenic overlap analysis were used to explore the shared genetic components between ADHD, ASD, and intelligence. Mendelian randomization (MR) analysis was used to examine the causal associations between ADHD, ASD, and intelligence. A cross-trait meta-analysis was performed to identify pleiotropic genetic variants across the three traits.
Our results showed that intelligence has a positive and negative genetic correlation with ASD and ADHD, respectively, including three hub genomic regions showing correlated genetic effects across the three traits. Polygenic overlap analysis indicated that all the risk variants contributing to ADHD are overlapped with half of those for intelligence, and the majority of the shared variants have opposite effect directions between them. The majority of risk variants (80%) of ASD are overlapped with almost all the risk variants of intelligence (97%). Notably, some ASD/intelligence overlapping variants displayed opposing effects on these two conditions. MR analysis showed that the genetic liability to higher intelligence was associated with an increased risk for ASD (OR = 1.12) and a decreased risk for ADHD (OR = 0.78). Cross-trait meta-analyses identified 170 pleiotropic genomic loci across the three traits, including 12 novel loci. Functional analyses of the novel genes support their potential involvement in neurodevelopment.
Our results suggest that ADHD is associated with inheriting a reduced set of low-intelligence alleles, whereas ASD results from incongruous effects from a mixture of high-intelligence and low-intelligence contributing alleles summed up with additional, ASD-specific risk variants not associated with intelligence.
注意力缺陷多动障碍（ADHD）和自闭症谱系障碍（ASD）常同时出现；这两种特质都会对智力得分产生影响。这三种特质之间的遗传关系尚不清楚。
使用注意力缺陷多动障碍（20183例病例和35191例对照）、自闭症谱系障碍（18381例病例和27969例对照）和智力（269867名参与者）的全基因组关联研究的汇总结果进行分析。采用局部遗传相关性分析和多基因重叠分析来探索注意力缺陷多动障碍、自闭症谱系障碍和智力之间共享的遗传成分。采用孟德尔随机化（MR）分析来检验注意力缺陷多动障碍、自闭症谱系障碍和智力之间的因果关联。进行跨性状荟萃分析以识别这三种特质中的多效性基因变异。
我们的结果表明，智力与自闭症谱系障碍和注意力缺陷多动障碍分别存在正负遗传相关性，包括三个枢纽基因组区域在这三种特质中显示出相关的遗传效应。多基因重叠分析表明，所有导致注意力缺陷多动障碍的风险变异与一半的智力风险变异重叠，并且大多数共享变异在它们之间具有相反的效应方向。自闭症谱系障碍的大多数风险变异（80%）与几乎所有智力风险变异（97%）重叠。值得注意的是，一些自闭症谱系障碍/智力重叠变异对这两种情况显示出相反的影响。孟德尔随机化分析表明，较高智力的遗传易感性与自闭症谱系障碍风险增加（比值比=1.12）和注意力缺陷多动障碍风险降低（比值比=0.78）相关。跨性状荟萃分析确定了这三种特质中的170个多效性基因组位点，包括12个新位点。对新基因的功能分析支持它们可能参与神经发育。
我们的结果表明，注意力缺陷多动障碍与遗传较少的低智力等位基因有关，而自闭症谱系障碍是由高智力和低智力贡献等位基因混合产生的不协调效应，再加上与智力无关的额外自闭症谱系障碍特异性风险变异所致。
