A meta-analysis of rare copy number variants associated with autismand schizophrenia Pubblico

Abstract

Autism spectrum disorder (ASD) and schizophrenia have been associated with considerable phenotypic overlap and substantial heterogeneity within diagnostic categories, complicating current diagnostic practices. Genomic studies have identified shared sets of rare copy number variant (CNV) loci associated with these disorders. Recently, an increasing number of whole-genome analyses of large sample sizes have been conducted. To better understand the underlying genetic architecture of these disorders, a meta-analysis was conducted to synthesize data from rare variant analyses of CNV loci associated with increased risk of ASD and schizophrenia. A search of PubMed for case-control studies identifying CNVs associated with the disorders identified 369 schizophrenia studies and 346 ASD studies. Seven ASD studies and 19 schizophrenia studies remained after implementation of inclusion criteria. Data were extracted for 11 CNV loci and effect sizes expressed as CMH odds ratios. Duplications at 22q11.2 (p-value SCZ = 2.2E-16; ASD = 0.0058) and deletions at 15q11.2-13 (p-value SCZ = 0.0018; ASD = 2.8E-06) were associated with increased risk for both schizophrenia and autism. Reciprocal relationships were observed for mutations at 16p11.2 (p-value SCZ duplication = 9.7E-16; ASD deletion = 0.026) and 1q21.1 (p-value SCZ deletion = 6.9E-14; ASD duplication = 0.03). For ASD, 22q11.2 deletions (CMH OR: 11.2, 95% CI: 1.6 - 486.8) displayed the strongest association, while 3q29 deletions (CMH OR: 38.8, 95% CI: 5.2 - 1873.3) displayed the strongest association with schizophrenia. These analyses further support an overlap in CNV loci associated with ASD and schizophrenia and provide further evidence to support the need for an evaluation of the current system of psychiatric classification. However, further analysis of the underlying genetic architecture associated with phenotypes common to both autism and schizophrenia as well as potential environmental influences is necessary in order to better understand the relationship between ASD and schizophrenia.

Table of Contents

Background/Literature Review............. 2

Methods................................................ 7

Search Strategy..................................... 7

Selection Criteria and Study Selection..7

Data Extraction.................................... 8

Data Analysis....................................... 8

Results................................................. 9

Literature Search................................. 9

Study Characteristics........................... 9

Main Analysis....................................... 9

Deletions.............................................. 9

Duplications......................................... 10

Deletions and Duplications Combined..10

Sensitivity Analysis............................. 11

Discussion............................................ 13

Limitations........................................... 15

Strengths.............................................. 15

Tables................................................... 17

Table 1. Intervals of selected copy number variants (CNVs).. 17

Table 2. Descriptions of each study included in analysis.. 17

Table 3. CMH-adjusted odds ratios for each region separated by deletion/duplication classification as well as combined.. 18

Table 4. Pooled data for regions with shared significant CMH-adjusted odds ratios.. 20

Table 5. Leave-one-out sensitivity analysis results for pooled autism data.. 22

Table 6. Leave-one-out sensitivity analysis results for pooled schizophrenia data.. 22

Figures................................................... 25

Figure 1. Flowcharts of search strategy and study identification for (a) autism and (b) schizophrenia.. 25

References............................................ 26

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Degree	MSPH
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Health Sciences, Epidemiology
Parola chiave	copy number variant autism CNV Autism Spectrum Disorder schizophrenia ASD
Committee Chair / Thesis Advisor	Mulle, Jennifer, Emory University

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