Nath Swapan K, Kelly Jennifer A, Reid Jeff, Lam Tom, Gray-McGuire Courtney, Namjou Bahram, Aston Christopher E, Harley John B
Genetic Epidemiology Unit, Oklahoma Medical Research Foundation, Oklahoma City, USA.
Hum Genet. 2002 Jul;111(1):54-8. doi: 10.1007/s00439-002-0743-1. Epub 2002 Jun 14.
Seizures and psychosis are neuropsychiatric (NP) manifestations of a large number of systemic lupus erythematosus (SLE) patients. Since NP manifestations were part of the SLE phenotype for some, but not all SLE affecteds, we hypothesized that those SLE patient families with NP manifestations might be more genetically homogeneous at loci important to NP-related SLE, and hence have increased power to detect linkage. We identified 23 families of European-American (EA) origin and 20 families of African-American (AA) origin, in which at least one SLE patient in each family was diagnosed with the presence of NP manifestations. A total of 318 microsatellite markers at an average marker density of 11 cM were genotyped. Uncertainty of the genetic model led us to perform the initial genome scan by a multipoint non-parametric allele sharing linkage method. Once the evidence of linkage was suggestive, we then performed parametric model-based linkage by maximizing the relevant parameters to define a parsimonious genetic model. We found the maximum multipoint parametric LOD score was 5.19 and the non-parametric linkage score (Zlr) was 3.12 ( P=9x10(-4)) for EA NP pedigrees at 4p16, previously identified as SLEB3. The segregation behavior of this linked locus suggests a dominant mode of inheritance with an almost 100% homogeneous genetic effect in these pedigrees. The results demonstrated a significant increase of LOD score to detect SLEB3 when the families were further ascertained through NP, compared with the analysis of all EA SLE families together.
癫痫发作和精神病是大量系统性红斑狼疮（SLE）患者的神经精神（NP）表现。由于NP表现是部分而非全部SLE患者的SLE表型的一部分，我们推测那些有NP表现的SLE患者家系在对NP相关SLE重要的基因座上可能在遗传上更加同质，因此具有更强的检测连锁的能力。我们确定了23个欧美（EA）血统的家系和20个非裔美国（AA）血统的家系，每个家系中至少有一名SLE患者被诊断有NP表现。对总共318个平均标记密度为11厘摩的微卫星标记进行了基因分型。遗传模型的不确定性使我们通过多点非参数等位基因共享连锁方法进行初始全基因组扫描。一旦连锁证据具有提示性，我们随后通过最大化相关参数来执行基于参数模型的连锁分析，以定义一个简约的遗传模型。我们发现，对于先前确定为SLEB3的4p16处的EA NP家系，最大多点参数LOD分数为5.19，非参数连锁分数（Zlr）为3.12（P = 9×10⁻⁴）。这个连锁基因座的分离行为表明在这些家系中存在一种显性遗传模式，其遗传效应几乎100%同质。结果表明，与对所有EA SLE家系一起进行分析相比，当通过NP进一步确定家系时，检测SLEB3的LOD分数显著增加。
