Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Human Genetics Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, 20892, USA.
Transl Psychiatry. 2018 Oct 12;8(1):218. doi: 10.1038/s41398-018-0226-3.
Bipolar disorder (BD) is a mental disorder characterized by alternating periods of depression and mania. Individuals with BD have higher levels of early mortality than the general population, and a substantial proportion of this is due to increased risk for comorbid diseases. To identify the molecular events that underlie BD and related medical comorbidities, we generated imputed whole-genome sequence data using a population-specific reference panel for an extended multigenerational Old Order Amish pedigree (n = 394), segregating BD and related disorders. First, we investigated all putative disease-causing variants at known Mendelian disease loci present in this pedigree. Second, we performed genomic profiling using polygenic risk scores (PRS) to establish each individual's risk for several complex diseases. We identified a set of Mendelian variants that co-occur in individuals with BD more frequently than their unaffected family members, including the R3527Q mutation in APOB associated with hypercholesterolemia. Using PRS, we demonstrated that BD individuals from this pedigree were enriched for the same common risk alleles for BD as the general population (β = 0.416, p = 6 × 10). Furthermore, we find evidence for a common genetic etiology between BD risk and polygenic risk for clinical autoimmune thyroid disease (p = 1 × 10), diabetes (p = 1 × 10), and lipid traits such as triglyceride levels (p = 3 × 10) in the pedigree. We identify genomic regions that contribute to the differences between BD individuals and unaffected family members by calculating local genetic risk for independent LD blocks. Our findings provide evidence for the extensive genetic pleiotropy that can drive epidemiological findings of comorbidities between diseases and other complex traits.
双相情感障碍（BD）是一种以抑郁和躁狂交替发作为特征的精神障碍。BD 患者的早逝率高于一般人群，而其中很大一部分是由于合并疾病风险增加所致。为了确定BD 及相关合并症的潜在分子事件，我们使用特定于人群的参考面板为一个扩展的多世代旧秩序阿米什家系（n=394）生成了全基因组序列数据，该家系存在BD 和相关疾病。首先，我们研究了该家系中存在的所有已知孟德尔疾病基因座的潜在致病变体。其次，我们使用多基因风险评分（PRS）进行基因组分析，以确定每个个体患有几种复杂疾病的风险。我们确定了一组在 BD 患者中比未受影响的家庭成员更频繁共现的孟德尔变体，包括与高胆固醇血症相关的 APOB 中的 R3527Q 突变。使用PRS，我们证明了该家系中的 BD 个体与一般人群一样，BD 的常见风险等位基因更为丰富（β=0.416，p=6×10）。此外，我们在家系中发现了BD 风险和临床自身免疫性甲状腺疾病（p=1×10）、糖尿病（p=1×10）和脂质特征（如甘油三酯水平，p=3×10）的多基因风险之间存在共同遗传病因的证据。我们通过计算独立 LD 块的局部遗传风险，确定了导致 BD 个体与未受影响的家庭成员之间差异的基因组区域。我们的研究结果为疾病和其他复杂特征之间合并症的流行病学发现提供了广泛遗传多效性的证据。
