Supplementary Material for: The Value of Regenotyping Older Linkage Data Sets with Denser Marker Panels

Objectives: Linkage analysis can help determine regions of interest in whole-genome sequence studies. However, many linkage studies rely on older microsatellite (MSAT) panels. We set out to determine whether results would change if we regenotyped families using a dense map of SNPs. Methods: We selected 47 Hispanic-American families from the NIMH Repository and Genomics Resource (NRGR) schizophrenia data repository. We regenotyped all individuals with DNA available from the NRGR on the Affymetrix Lat Array. After optimizing SNP selection for inclusion on the linkage map, we compared information content (IC) and linkage results using MSAT, SNP and MSAT+SNP maps. Results: As expected, SNP provided a higher average IC (0.78, SD 0.03) than MSAT (0.51, SD 0.10) in a direct ‘apples-to-apples' comparison using only individuals genotyped on both platforms; while MSAT+SNP provided only a slightly higher IC (0.82, SD 0.03). However, when utilizing all available individuals, including those who had genotypes available on only one platform, the IC was substantially increased using MSAT+SNP (0.76, SD 0.05) compared to SNP (0.61, SD 0.02). Linkage results changed appreciably between MSAT and MSAT+SNP in terms of magnitude, rank ordering and localization of peaks. Conclusions: Regenotyping older family data can substantially alter the conclusions of linkage analyses.研究目的：连锁分析可助力全基因组测序研究中目标区域的定位，但当前多数连锁研究仍依赖于较早的微卫星（microsatellite, MSAT）分型面板。本研究旨在探究，若使用高密度单核苷酸多态性（single nucleotide polymorphism, SNP）图谱对家系进行重分型，研究结果是否会发生改变。 研究方法：我们从美国国立精神卫生研究所（National Institute of Mental Health, NIMH）样本库与基因组资源中心（Repository and Genomics Resource, NRGR）的精神分裂症数据资源库中，筛选纳入47个西班牙裔美国家系。针对该资源库中留存有DNA样本的全部个体，我们采用Affymetrix Lat Array芯片完成重分型。在优化用于构建连锁图谱的SNP筛选策略后，我们分别基于微卫星图谱、SNP图谱以及微卫星+SNP整合图谱，对比了信息含量（information content, IC）与连锁分析结果。 研究结果：正如预期，在仅使用两种平台均完成分型的个体开展直接对等比对时，SNP图谱的平均信息含量（0.78，标准差（standard deviation, SD）0.03）高于微卫星图谱（0.51，标准差0.10）；而微卫星+SNP整合图谱的信息含量仅略有提升（0.82，标准差0.03）。但当纳入所有可用个体（包括仅在单一平台完成分型的个体）进行分析时，相较于SNP图谱（0.61，标准差0.02），使用微卫星+SNP整合图谱的信息含量显著升高（0.76，标准差0.05）。在连锁分析结果层面，微卫星图谱与微卫星+SNP整合图谱的峰值强度、排名排序及位点定位均出现了显著变化。 研究结论：对既往家系数据进行重分型，可显著改变连锁分析的研究结论。