Genome-wide mediation analysis of psychiatric and cognitive traits through imaging phenotypes

Xuan Bi, Liuqing Yang, Tengfei Li, Baisong Wang, Hongtu Zhu, Heping Zhang

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Heritability is well documented for psychiatric disorders and cognitive abilities which are, however, complex, involving both genetic and environmental factors. Hence, it remains challenging to discover which and how genetic variations contribute to such complex traits. In this article, they propose to use mediation analysis to bridge this gap, where neuroimaging phenotypes were utilized as intermediate variables. The Philadelphia Neurodevelopmental Cohort was investigated using genome-wide association studies (GWAS) and mediation analyses. Specifically, 951 participants were included with age ranging from 8 to 21 years. Two hundred and four neuroimaging measures were extracted from structural magnetic resonance imaging scans. GWAS were conducted for each measure to evaluate the SNP-based heritability. Furthermore, mediation analyses were employed to understand the mechanisms in which genetic variants have influence on pathological behaviors implicitly through neuroimaging phenotypes, and identified SNPs that would not be detected otherwise. Our analyses found that rs10494561, located in the intron region within NMNAT2, was associated with the severity of the prodromal symptoms of psychosis implicitly, mediated through the volume of the left hemisphere of the superior frontal region (P=2.38×10-8). The gene NMNAT2 is known to be associated with brainstem degeneration, and produce cytoplasmic enzyme which is mainly expressed in the brain. Another SNP rs2285351 was found in the intron region of gene IFT122 which may be potentially associated with human spatial orientation ability through the area of the left hemisphere of the isthmuscingulate region (P=3.70×10-8). Hum Brain Mapp 38:4088–4097, 2017.

Original languageEnglish (US)
Pages (from-to)4088-4097
Number of pages10
JournalHuman Brain Mapping
Volume38
Issue number8
DOIs
StatePublished - Aug 2017
Externally publishedYes

Bibliographical note

Funding Information:
We thank Chintan M. Mehta for providing useful information about genetic data analysis. We also greatly appreciate the time and effort that the participants and their families spent at the Philadelphia Neurodevelopmental Cohort. Support for the collection of the data sets was provided by NIH grant RC2MH089983 awarded to Raquel Gur and RC2MH089924 awarded to Hakon Hakonarson. All subjects were recruited through the Center for Applied Genomics at The Children's Hospital in Philadelphia. The data sets used in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id = phs000607.v1.p1 through dbGaP accession: phs000607.v1.p1.

Keywords

  • genome-wide association studies
  • imaging genetics
  • intermediate phenotypes
  • neuroimaging measures

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