Background/Objectives: Family history is a known risk factor for multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). Previous genome-wide association studies (GWASs) have identified 35 common loci associated with MM risk and 21 associated with MGUS. The objective of this study was to identify less common and rare genetic loci predisposing to MM/MGUS through whole-exome sequencing (WES)-based linkage analysis. Methods:Multipoint linkage analysis was conducted using the Multipoint Engine for Rapid Likelihood Inference (MERLIN) with the Lander–Green algorithm on germline WES data from 79 pedigrees with 2 or more affected relatives (120 MM, 86 MGUS, and 21 unaffected). Genome-wide linkage was evaluated using 12,946 independent single-nucleotide variants (linkage disequilibrium r2< 0.05). Results: Significant linkage was observed at chromosome 6q22.33–q24.2 by the non-parametric model (logarithm-of-odds (LOD) = 3.3) and suggestive linkage by the dominant parametric model (heterogeneity LOD (HLOD) = 2.5). Fourteen rare variants within this region were prioritized using family-specific partial LOD scores and in silico functional prediction tools. Nine of these variants,REPS1,THEMIS,TAAR6,AHI1,VNN1,VNN3,MTFR2/FAM54A,LAMA2, andPHACTR2, overlapped immune-regulatory regions in blood cell lines and were not previously identified in GWASs. Conclusions: This study demonstrates the utility of applying a linkage analysis framework to familial WES data for identifying genomic regions and candidate genes that may contribute to MM/MGUS predisposition. These findings provide new insight into the inherited risk and etiology of familial MM and MGUS.
背景/目的：家族史是多发性骨髓瘤（MM）及其前驱状态——意义未明的单克隆丙种球蛋白病（MGUS）的已知风险因素。既往全基因组关联研究（GWAS）已鉴定出35个与MM风险相关的常见基因座和21个与MGUS相关的基因座。本研究旨在通过基于全外显子组测序（WES）的连锁分析，识别与MM/MGUS易感性相关的较不常见及罕见基因位点。方法：使用基于Lander-Green算法的快速似然推断多点引擎（MERLIN），对来自79个包含2名或以上患病亲属（120例MM，86例MGUS，21例未患病）家系的种系WES数据进行多点连锁分析。使用12,946个独立的单核苷酸变异（连锁不平衡r² < 0.05）评估全基因组连锁。结果：非参数模型在染色体6q22.33–q24.2区域观察到显著连锁（对数优势比（LOD）= 3.3），显性参数模型提示存在连锁（异质性LOD（HLOD）= 2.5）。利用家系特异性部分LOD评分和计算机功能预测工具，优先分析了该区域内的14个罕见变异。其中9个变异（REPS1、THEMIS、TAAR6、AHI1、VNN1、VNN3、MTFR2/FAM54A、LAMA2和PHACTR2）与血细胞系中的免疫调控区域重叠，且此前未在GWAS中被识别。结论：本研究证明了将连锁分析框架应用于家族性WES数据，对于识别可能影响MM/MGUS易感性的基因组区域和候选基因具有实用价值。这些发现为家族性MM和MGUS的遗传风险及病因学提供了新的见解。
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