Bigdeli T Bernard, Bacanu Silviu-Alin, Webb Bradley T, Walsh Dermot, O'Neill F Anthony, Fanous Ayman H, Riley Brien P, Kendler Kenneth S
*To whom correspondence should be addressed; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics of VCU, Box 980126, Richmond, VA 23298-0126, US; tel: (804)-828-8590, fax: (804)-828-1471, e-mail:
Schizophr Bull. 2014 Jan;40(1):60-5. doi: 10.1093/schbul/sbt122. Epub 2013 Aug 22.
Early descriptive work and controlled family and adoption studies support the hypothesis that a range of personality and nonschizophrenic psychotic disorders aggregate in families of schizophrenic probands. Can we validate, using molecular polygene scores from genome-wide association studies (GWAS), this schizophrenia spectrum?
The predictive value of polygenic findings reported by the Psychiatric GWAS Consortium (PGC) was applied to 4 groups of relatives from the Irish Study of High-Density Schizophrenia Families (ISHDSF; N = 836) differing on their assignment within the schizophrenia spectrum. Genome-wide single nucleotide polymorphism data for affected and unaffected relatives were used to construct per-individual polygene risk scores based on the PGC stage-I results. We compared mean polygene scores in the ISHDSF with mean scores in ethnically matched population controls (N = 929).
The schizophrenia polygene score differed significantly across diagnostic categories and was highest in those with narrow schizophrenia spectrum, lowest in those with no psychiatric illness, and in-between in those classified in the intermediate, broad, and very broad schizophrenia spectrum. Relatives of all of these groups of affected subjects, including those with no diagnosis, had schizophrenia polygene scores significantly higher than the control sample.
In the relatives of high-density families, the observed pattern of enrichment of molecular indices of schizophrenia risk suggests an underlying, continuous liability distribution and validates, using aggregate common risk alleles, a genetic basis for the schizophrenia spectrum disorders. In addition, as predicted by genetic theory, nonpsychotic members of multiply-affected schizophrenia families are significantly enriched for replicated, polygenic risk variants compared with the general population.
早期的描述性研究以及对照的家族和收养研究支持这样一种假说，即一系列人格障碍和非精神分裂症性精神障碍在精神分裂症先证者的家族中聚集。我们能否使用全基因组关联研究（GWAS）的分子多基因分数来验证这种精神分裂症谱系？
将精神病学GWAS联盟（PGC）报告的多基因研究结果的预测价值应用于来自爱尔兰高密度精神分裂症家族研究（ISHDSF；N = 836）的4组亲属，这些亲属在精神分裂症谱系中的分类不同。利用患病和未患病亲属的全基因组单核苷酸多态性数据，根据PGC第一阶段的结果构建个体多基因风险分数。我们将ISHDSF中的平均多基因分数与种族匹配的人群对照（N = 929）中的平均分数进行比较。
精神分裂症多基因分数在不同诊断类别之间存在显著差异，在狭义精神分裂症谱系患者中最高，在无精神疾病者中最低，在中度、广义和极广义精神分裂症谱系患者中处于两者之间。所有这些受影响受试者组的亲属，包括未确诊者，其精神分裂症多基因分数均显著高于对照样本。
在高密度家族的亲属中，观察到的精神分裂症风险分子指标富集模式提示存在潜在的连续易感性分布，并使用聚合的常见风险等位基因验证了精神分裂症谱系障碍的遗传基础。此外，正如遗传理论所预测的，与一般人群相比，多重患病的精神分裂症家族中的非精神病成员显著富集了重复的多基因风险变异。
