Haplotype phasing of a bipolar disorder pedigree revealed rare multiple mutations of SPOCD1 gene in the 1p36-35 susceptibility locus.
Haplotype phasing of a bipolar disorder pedigree revealed rare multiple mutations of SPOCD1 gene in the 1p36-35 susceptibility locus.
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DOI：
10.1016/j.jad.2022.04.150
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发表时间：
2022-04
影响因子：
6.6
通讯作者：
Gakuya Takamatsu;K. Yanagi;Kae Koganebuchi;Fuyuko Yoshida;Jun-Seok Lee;K. Toyama;K. Hattori;Chiaki Katagiri;T. Kondo;H. Kunugi;R. Kimura;T. Kaname;Masayuki Matsushita
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文献类型：
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作者：
Gakuya Takamatsu;K. Yanagi;Kae Koganebuchi;Fuyuko Yoshida;Jun-Seok Lee;K. Toyama;K. Hattori;Chiaki Katagiri;T. Kondo;H. Kunugi;R. Kimura;T. Kaname;Masayuki Matsushita
背景双相情感障碍（BD）的病因尚不清楚。考虑到双相障碍的复杂性，专注于特定位点单倍型的基于家系的测序研究可能有助于发现高影响风险变异。本研究全面检查了1p36-35 BD和复发性抑郁症（RDD）易感位点的单倍型序列。方法对日本冲绳的BD家庭进行调查。我们进行了连锁分析，并利用全基因组测序确定了受影响的单倍型的阶段序列。我们在单倍型上过滤了罕见的错义变异。为了验证，我们对大约3000名日本受试者进行了病例对照遗传关联研究。结果我们鉴定出了一个具有BD和RDD的三代多重谱系。引人注目的是，我们在1p36-35之间发现了与情绪障碍的显著联系（几率对数[LOD] = 3.61），这在其他祖先研究中得到了支持。最后，我们确定了所有受影响受试者共有的6.4 mb单倍型的整个序列。此外，我们在单倍型的thespocd1基因上发现了罕见的三联体错义变异。值得注意的是，尽管频率罕见，但在88个独立的BD I型基因分型样本中发现了一个具有多个espocd1变异体的杂合子。重复样本很小。短读测序可能会遗漏结构变异。未分析多基因风险评分。结论1p36-35单倍型序列对今后BD变异的研究具有一定的价值。特别是，spocd1是一个有希望的候选基因，应该得到验证。
BackgroundThe etiology of bipolar disorder (BD) is poorly understood. Considering the complexity of BD, pedigree-based sequencing studies focusing on haplotypes at specific loci may be practical to discover high-impact risk variants. This study comprehensively examined the haplotype sequence at 1p36–35 BD and recurrent depressive disorder (RDD) susceptibility loci.MethodsWe surveyed BD families in Okinawa, Japan. We performed linkage analysis and determined the phased sequence of the affected haplotype using whole genome sequencing. We filtered rare missense variants on the haplotype. For validation, we conducted a case-control genetic association study on approximately 3000 Japanese subjects.ResultsWe identified a three-generation multiplex pedigree with BD and RDD. Strikingly, we identified a significant linkage with mood disorders (logarithm of odds [LOD] = 3.61) at 1p36–35, supported in other ancestry studies. Finally, we determined the entire sequence of the 6.4-Mb haplotype shared by all affected subjects. Moreover, we found a rare triplet of missense variants in theSPOCD1gene on the haplotype. Notably, despite the rare frequency, one heterozygote with multipleSPOCD1variants was identified in an independent set of 88 BD type I genotyping samples.Limitations.The 1p36–35 sequence was obtained from only a single pedigree. The replicate sample was small. Short-read sequencing might miss structural variants. A polygenic risk score was not analyzed.ConclusionThe 1p36–35 haplotype sequence may be valuable for future BD variant studies. In particular,SPOCD1is a promising candidate gene and should be validated.