To analyze pedigrees with quantitative trait (QT) and sequence data, we developed a rare variant (RV) quantitative nonparametric linkage (QNPL) method, which evaluates sharing of minor alleles. RV-QNPL has greater power than the traditional QNPL that tests for excess sharing of minor and major alleles. RV-QNPL is robust to population substructure and admixture, locus heterogeneity, and inclusion of nonpathogenic variants and can be readily applied outside of coding regions. When QNPL was used to analyze common variants, it often led to loci mapping to large intervals, e.g., >40 Mb. In contrast, when RVs are analyzed, regions are well defined, e.g., a gene. Using simulation studies, we demonstrate that RV-QNPL is substantially more powerful than applying traditional QNPL methods to analyze RVs. RV-QNPL was also applied to analyze age-at-onset (AAO) data for 107 late-onset Alzheimer’s disease (LOAD) pedigrees of Caribbean Hispanic and European ancestry with whole-genome sequence data. When AAO of AD was analyzed regardless of APOE ε4 status, suggestive linkage (LOD = 2.4) was observed with RVs in KNDC1 and nominally significant linkage (p < 0.05) was observed with RVs in LOAD genes ABCA7 and IQCK. When AAO of AD was analyzed for APOE ε4 positive family members, nominally significant linkage was observed with RVs in APOE, while when AAO of AD was analyzed for APOE ε4 negative family members, nominal significance was observed for IQCK and ADAMTS1. RV-QNPL provides a powerful resource to analyze QTs in families to elucidate their genetic etiology.

为了分析具有数量性状 (QT) 和序列数据的家系，我们开发了一种罕见变异 (RV) 定量非参数连锁 (QNPL) 方法，用于评估次要等位基因的共享。RV-QNPL 比测试次要和主要等位基因过度共享的传统 QNPL 具有更大的功效。RV-QNPL 对种群亚结构和混合物、基因座异质性和非致病性变异的包含具有稳健性，并且可以很容易地应用于编码区域之外。当 QNPL 用于分析常见变异时，通常会导致基因座映射到较大的间隔，例如 >40 Mb。相反，当分析 RV 时，区域是明确定义的，例如基因。通过模拟研究，我们证明 RV-QNPL 比应用传统 QNPL 方法分析 RV 更强大。RV-QNPL 还用于分析具有全基因组序列数据的加勒比西班牙裔和欧洲血统的 107 个迟发性阿尔茨海默病 (LOAD) 家系的发病年龄 (AAO) 数据。当分析 AD 的 AAO 时，无论APOE ε4 状态、提示性连锁 (LOD = 2.4) 在KNDC1中与 RV 一起观察到，在 LOAD 基因ABCA7和IQCK 中与 RV 一起观察到名义上显着的连锁 ( p < 0.05) 。当针对APOE ε4 阳性家族成员分析 AD 的 AAO 时，观察到与APOE中的 RV 具有名义上显着的联系，而当针对APOE ε4 阴性家族成员分析 AD 的 AAO 时，观察到IQCK和ADAMTS1具有名义上的显着性。RV-QNPL 为分析家族中的 QT 以阐明其遗传病因提供了强大的资源。