Ordered subsets linkage analysis of antisocial behavior in substance use disorder among participants in the collaborative study on the genetics of alcoholism

Abstract

Heterogeneity in complex diseases such as Substance Use Disorder (SUD) reduces the power to detect linkage and makes replication of findings in other populations unlikely. It is therefore critical to refine the phenotype and use methods that account for genetic heterogeneity between families. SUD was operationalized as diagnosis of abuse or dependence to alcohol and/or any one of five illicit substances. Whole-genome linkage analysis of 241 extended pedigree families from the Collaborative Study on the Genetics of Alcoholism was performed in Merlin using an affected sibship design. An Ordered Subsets Analysis (OSA) using FLOSS sought to increase the homogeneity of the sample by ranking families by their density of childhood and adult antisocial behaviors, producing new maximum Nonparametric Lod (NPL) scores on each chromosome for each subset of families. Prior to OSA, modest evidence for linkage was found on chromosomes 8 and 17. Although changes in NPL scores were not statistically significant, OSA revealed possible evidence of linkages on chromosome 7, near markers D7S1795 and D7S821. NPL scores >3.0 were also observed on chromosomes 2, 3, 5, 9, and 14. However, the number of families used in these latter subsets for linkage may be too small to be meaningful. Results provide some evidence for the ability of OSA to reduce genetic heterogeneity, and add further support to chromosome 7 as a possible location to search for genes related to various SUD related processes. Nonetheless, replication of these results in other samples is essential.

The multidimensionality of schizotypy in nonpsychotic relatives of patients with schizophrenia and its applications in ordered subsets linkage analysis of schizophrenia

“…Second, since Social Isolation/Introversion was identified by fewer than three items, it may be underidentified. Third, although the OSA procedure estimates the statistical significance of the change in NPL-Z score from the subsets based on permutation techniques, it does not provide a statistical estimate of the significance of the new NPL-Z score itself, and hence cannot calculate a new NPL-Z score based on reduced genetic heterogeneity at a specific region of a priori interest [Jacobson et al, 2008]. Further fine mapping studies on these regions are required to confirm our findings.…”

Processing, properties, and in vitro bioactivity of polysulfone‐bioactive glass composites

“…Second, since Social Isolation/Introversion was identified by fewer than three items, it may be underidentified. Third, although the OSA procedure estimates the statistical significance of the change in NPL‐ Z score from the subsets based on permutation techniques, it does not provide a statistical estimate of the significance of the new NPL‐ Z score itself, and hence cannot calculate a new NPL‐ Z score based on reduced genetic heterogeneity at a specific region of a priori interest [Jacobson et al, 2008]. Further fine mapping studies on these regions are required to confirm our findings.…”

Neuropsychological Measures of Executive Function and Antisocial Behavior: A Meta-Analysis*

“…It is important for studies to control for such factors when examining the association between ASB and EF, although efforts to do so have been inconsistent. For example, some evidence suggests that EF impairments are associated with both substance use disorders (Giancola, Shoal, and Mezzich, 2001) and ADHD (Willcutt et al, 2005), which are both highly prevalent among antisocial individuals (Jacobson et al, 2008; Van Goozen et al, 2007). However, few studies have explicitly controlled for or examined the mediating or moderating effects these factors may have on the association between ASB and EF.…”