期刊
PSYCHOLOGICAL MEDICINE
卷 46, 期 7, 页码 1523-1534出版社
CAMBRIDGE UNIV PRESS
DOI: 10.1017/S0033291716000167
关键词
First-episode patients; functional connectivity; genome-wide association studies; schizophrenia
资金
- National Nature Science Foundation of China [81130024, 81271479]
- National Key Technology R & D Program of the Ministry of Science and Technology of China during the 12th Five-Year Plan [2012BAI01B06]
- National Natural Science Foundation of China/Research Grants Council of Hong Kong Joint Research Scheme [8141101084N HKU736/14]
- '135' Project of Building Top Disciplines in China of West China Hospital, Sichuan University
- Sichuan University
- Hong Kong Health and Medical Research Fund [02132236]
Background. The genetic influences in human brain structure and function and impaired functional connectivities are the hallmarks of the schizophrenic brain. To explore how common genetic variants affect the connectivities in schizophrenia, we applied genome-wide association studies assaying the abnormal neural connectivities in schizophrenia as quantitative traits. Method. We recruited 161 first-onset and treatment-naive patients with schizophrenia and 150 healthy controls. All the participants underwent scanning with a 3 T-magnetic resonance imaging scanner to acquire structural and functional imaging data and genotyping using the HumanOmniZhongHua-8 BeadChip. The brain-wide association study approach was employed to account for the inherent modular nature of brain connectivities. Results. We found differences in four abnormal functional connectivities [left rectus to left thalamus (REC. L-THA. L), left rectus to right thalamus (REC. L-THA. R), left superior orbital cortex to left thalamus (ORBsup. L-THA. L) and left superior orbital cortex to right thalamus (ORBsup. L-THA. R)] between the two groups. Univariate single nucleotide polymorphism (SNP)-based association revealed that the SNP rs6800381, located nearest to the CHRM3 (cholinergic receptor, muscarinic 3) gene, reached genomic significance (p = 1.768 x 10(-8)) using REC. L-THA. R as the phenotype. Multivariate gene-based association revealed that the FAM12A (family with sequence similarity 12, member A) gene nearly reached genomic significance (nominal p = 2.22 x 10(-6), corrected p = 0.05). Conclusions. Overall, we identified the first evidence that the CHRM3 gene plays a role in abnormal thalamo-orbital frontal cortex functional connectivity in first-episode treatment-naive patients with schizophrenia. Identification of these genetic variants using neuroimaging genetics provides insights into the causes of variability in human brain development, and may help us determine the mechanisms of dysfunction in schizophrenia.
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