Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA.
Transl Psychiatry. 2020 Feb 24;10(1):74. doi: 10.1038/s41398-020-0758-1.
Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 838 individuals and high-coverage whole-genome sequencing of 449 individuals. We compared polygenic risk scores (PRS), estimated using the latest BP1 genome-wide association study (GWAS) summary statistics, between BP1 individuals and related controls. We also evaluated whether BP1 individuals had a higher burden of rare deleterious single-nucleotide variants (SNVs) and rare copy number variants (CNVs) in a set of genes related to BP1. We found that compared with unaffected relatives, BP1 individuals had higher PRS estimated from BP1 GWAS statistics (P = 0.001 ~ 0.007) and displayed modest increase in burdens of rare deleterious SNVs (P = 0.047) and rare CNVs (P = 0.002 ~ 0.033) in genes related to BP1. We did not observe rare variants segregating in the pedigrees. These results suggest that small-to-moderate effect rare and common variants are more likely to contribute to BP1 risk in these extended pedigrees than a few large-effect rare variants.
目前的病例对照研究证据表明，精神疾病的遗传风险主要来自许多常见的变异，每个变异的表型影响都很小。描述许多多代家系中双相情感障碍（BP）明显分离的文献表明，在这些家庭中，大效应遗传变异可能起更大的作用。为了确定罕见和常见变异对 BP 的作用，我们对 26 个哥伦比亚和哥斯达黎加家系进行了遗传分析，这些家系是为了确定双相情感障碍 1（BP1）而确定的，BP1 是 BP 中最严重和最具遗传性的形式。在这些家系中，我们对 838 个人进行了微阵列 SNP 基因分型，对 449 个人进行了高覆盖率全基因组测序。我们比较了使用最新的 BP1 全基因组关联研究（GWAS）汇总统计数据估计的多基因风险评分（PRS），在 BP1 个体和相关对照之间。我们还评估了 BP1 个体是否在一组与 BP1 相关的基因中具有更高的罕见有害单核苷酸变异（SNV）和罕见拷贝数变异（CNV）负担。我们发现，与未受影响的亲属相比，BP1 个体的 BP1 GWAS 统计数据估计的 PRS 更高（P = 0.001 ~ 0.007），并且在与 BP1 相关的基因中，罕见有害 SNV（P = 0.047）和罕见 CNV（P = 0.002 ~ 0.033）的负担也略有增加。我们没有观察到家系中分离的罕见变异。这些结果表明，在这些扩展的家系中，与少数几个大效应罕见变异相比，小到中等效应的罕见和常见变异更有可能导致 BP1 风险增加。
