Hargreaves A, Anney R, O'Dushlaine C, Nicodemus K K, Gill M, Corvin A, Morris D, Donohoe Gary
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience,Trinity College Dublin,Republic of Ireland.
Psychol Med. 2014 Jul;44(10):2177-87. doi: 10.1017/S0033291713002663. Epub 2013 Nov 28.
Genetic studies of single gene variants have been criticized as providing a simplistic characterization of the genetic basis of illness risk that ignores the effects of other variants within the same biological pathways. Of candidate biological pathways for schizophrenia (SZ), the cell adhesion molecule (CAM) pathway has repeatedly been linked to both psychosis and neurocognitive dysfunction. Here we tested, using risk allele scores derived from the Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ), whether alleles within the CAM pathway were correlated with poorer neuropsychological function in patients.
In total, 424 patients with psychosis were assessed in areas of cognitive ability typically found to be impaired in SZ: intelligence quotient, memory, working memory and attentional control. CAM pathway genes were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Alleles within these genes identified as significantly associated with SZ risk in the PGC-SCZ were then used to calculate a CAM pathway-based polygenic risk allele score for each patient and these scores were tested for association with cognitive ability.
Increased CAM pathway polygenic risk scores were significantly associated with poorer performance on measures of memory and attention, explaining 1-3% of variation on these measures. Notably, the most strongly associated single nucleotide polymorphism (SNP) in the CAM pathway (rs9272105 within HLA-DQA1) explained a similar amount of variance in attentional control, but not memory, as the polygenic risk analysis.
These data support a role for the CAM pathway in cognitive function, both at the level of individual SNPs and the wider pathway. In so doing these data highlight the value of pathway-based polygenic risk score studies as well as single gene studies for understanding SZ-associated deficits in cognition.
单基因变异的遗传学研究被批评为对疾病风险的遗传基础进行了过于简单化的描述，忽略了同一生物途径中其他变异的影响。在精神分裂症（SZ）的候选生物途径中，细胞粘附分子（CAM）途径反复与精神病和神经认知功能障碍相关联。在此，我们使用来自精神分裂症精神病基因组全基因组关联研究联盟（PGC-SZ）得出的风险等位基因分数，测试CAM途径内的等位基因是否与患者较差的神经心理功能相关。
总共对424名精神病患者在认知能力方面进行了评估，这些认知能力通常在SZ中会受损：智商、记忆、工作记忆和注意力控制。使用京都基因与基因组百科全书（KEGG）数据库鉴定CAM途径基因。然后，将这些基因中被鉴定为与PGC-SZ中的SZ风险显著相关的等位基因用于计算每个患者基于CAM途径的多基因风险等位基因分数，并测试这些分数与认知能力的关联。
CAM途径多基因风险分数的增加与记忆和注意力测量指标上较差的表现显著相关，解释了这些测量指标中1%-3%的变异。值得注意的是，CAM途径中最强烈相关的单核苷酸多态性（SNP）（HLA-DQA1内的rs9272105）在注意力控制方面解释的变异量与多基因风险分析相似，但在记忆方面则不然。
这些数据支持CAM途径在认知功能中的作用，无论是在单个SNP水平还是更广泛的途径水平。通过这样做，这些数据突出了基于途径的多基因风险分数研究以及单基因研究对于理解与SZ相关的认知缺陷的价值。
