Modeling hybrid traits for comorbidity and genetic studies of alcohol and nicotine co-dependence

Heping Zhang, Dungang Liu, Jiwei Zhao, Xuan Bi

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


We propose a novel multivariate model for analyzing hybrid traits and identifying genetic factors for comorbid conditions. Comorbidity is a common phenomenon in mental health in which an individual suffers from multiple disorders simultaneously. For example, in the Study of Addiction: Genetics and Environment (SAGE), alcohol and nicotine addiction were recorded through multiple assessments that we refer to as hybrid traits. Statistical inference for studying the genetic basis of hybrid traits has not been well developed. Recent rank-based methods have been utilized for conducting association analyses of hybrid traits but do not inform the strength or direction of effects. To overcome this limitation, a parametric modeling framework is imperative. Although such parametric frameworks have been proposed in theory, they are neither well developed nor extensively used in practice due to their reliance on complicated likelihood functions that have high computational complexity. Many existing parametric frameworks tend to instead use pseudo-likelihoods to reduce computational burdens. Here, we develop a model fitting algorithm for the full likelihood. Our extensive simulation studies demonstrate that inference based on the full likelihood can control the type-I error rate, and gains power and improves the effect size estimation when compared with several existing methods for hybrid models. These advantages remain even if the distribution of the latent variables is mis-specified. After analyzing the SAGE data, we identify three genetic variants (rs7672861, rs958331, rs879330) that are significantly associated with the comorbidity of alcohol and nicotine addiction at the chromosome-wide level. Moreover, our approach has greater power in this analysis than several existing methods for hybrid traits.Although the analysis of the SAGE data motivated us to develop the model, it can be broadly applied to analyze any hybrid responses.

Original languageEnglish (US)
Pages (from-to)2359-2378
Number of pages20
JournalAnnals of Applied Statistics
Issue number4
StatePublished - Dec 2018

Bibliographical note

Funding Information:
Supported by National Institute on Drug Abuse Grant R01 DA016750-09 and was completed when DL and JZ were postdoctoral associates at Yale University. The real data used in this manuscript were obtained from dbGaP at phs000092.v1.p1 (accession number phs000092.v1.p1). The data collection was funded by NIH Grants U01 HG004422, U01 HG004446, U10 AA008401, P01 CA089392, R01 DA013423, U01 HG004438, and HHSN268200782096C.

Publisher Copyright:
© 2018, Institute of Mathematical Statistics. All rights reserved.


  • Association
  • Comorbidity
  • EM algorithm
  • Latent variable
  • Ordinal outcome


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