Inherited genetic risk factors play a role in multiple myeloma (MM), yet considerable missing heritability exists. Rare risk variants at genome-wide association study (GWAS) loci are a new avenue to explore. Pleiotropy between lymphoid neoplasms (LNs) has been suggested in family history and genetic studies, but no studies have interrogated sequencing for pleiotropic genes or rare risk variants. Sequencing genetically enriched cases can help discover rarer variants. We analyzed exome sequencing in familial or early-onset MM cases to identify rare, functionally relevant variants near GWAS loci for a range of LNs. A total of 149 distinct and significant LN GWAS loci have been published. We identified six recurrent, rare, potentially deleterious variants within 5 kb of significant GWAS single nucleotide polymorphisms in 75 MM cases. Mutations were observed in BTNL2, EOMES, TNFRSF13B, IRF8, ACOXL and TSPAN32. All six genes replicated in an independent set of 255 early-onset MM or familial MM or precursor cases. Expansion of our analyses to the full length of these six genes resulted in a list of 39 rare and deleterious variants, seven of which segregated in MM families. Three genes also had significant rare variant burden in 733 sporadic MM cases compared with 935 control individuals: IRF8 (P = 1.0 × 10−6), EOMES (P = 6.0 × 10−6) and BTNL2 (P = 2.1 × 10−3). Together, our results implicate six genes in MM risk, provide support for genetic pleiotropy between LN subtypes and demonstrate the utility of sequencing genetically enriched cases to identify functionally relevant variants near GWAS loci.

中文翻译：

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淋巴肿瘤易感位点测序绘制了六个骨髓瘤风险基因


遗传性遗传风险因素在多发性骨髓瘤 (MM) 中发挥着重要作用，但存在相当大的遗传性缺失。全基因组关联研究 (GWAS) 位点的罕见风险变异是一个值得探索的新途径。家族史和遗传学研究表明淋巴肿瘤 (LN) 之间存在多效性，但没有研究对多效性基因或罕见风险变异的测序进行询问。对基因丰富的病例进行测序可以帮助发现更罕见的变异。我们分析了家族性或早发性多发性骨髓瘤病例的外显子组测序，以确定一系列 LN 的 GWAS 基因座附近罕见的、功能相关的变异。总共 149 个独特且重要的 LN GWAS 位点已发表。我们在 75 例 MM 病例中，在 5 kb 的显着 GWAS 单核苷酸多态性中发现了 6 个复发的、罕见的、潜在有害的变异。在 BTNL2、EOMES、TNFRSF13B、IRF8、ACOXL 和 TSPAN32 中观察到突变。所有 6 个基因在一组独立的 255 例早发 MM 或家族性 MM 或先兆病例中复制。我们将分析扩展到这 6 个基因的全长，得出了 39 个罕见且有害的变异的列表，其中 7 个在 MM 家族中分离。与 935 名对照个体相比，733 名散发性 MM 病例中的三个基因也具有显着的罕见变异负担：IRF8 (P = 1.0 × 10−6)、EOMES (P = 6.0 × 10−6) 和 BTNL2 (P = 2.1 × 10−3) ）。总之，我们的结果暗示了 MM 风险中的 6 个基因，为 LN 亚型之间的遗传多效性提供了支持，并证明了对遗传富集病例进行测序以识别 GWAS 位点附近功能相关变异的效用。