Madhusudan Gujral | Search bioRxiv

bioRxiv2016

A contribution of novel CNVs to schizophrenia from a genome-wide study of 41,321 subjects

Genomic copy number variants (CNVs) have been strongly implicated in the etiology of schizophrenia (SCZ). However, apart from a small number of risk variants, elucidation of the CNV contribution to risk has been difficult due to the rarity of risk alleles, all occurring in less than 1% of cases. We sought to address this obstacle through a collaborative effort in which we applied a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. We observed a global enrichment of CNV burden in cases (OR=1.11, P=5.7e-15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7e-6). CNV burden is also enriched for genes associated with synaptic function (OR = 1.68, P = 2.8e-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P=7.3e-5). We identified genome-wide significant support for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. We find support at a suggestive level for nine additional candidate susceptibility and protective loci, which consist predominantly of CNVs mediated by non-allelic homologous recombination (NAHR).

Genetics↗

bioRxiv2015

Frequency and complexity of de novo structural mutation in autism

Genetic studies of Autism Spectrum Disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variation (SV) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping and de novo assembly to genome sequencing of 235 subjects, 71 cases, 26 sibling controls and their parents, we present an atlas of 1.2 million SVs (5,213/genome), comprising 11 different classes. We demonstrate a high diversity of de novo mutations, a majority of which were undetectable by previous methods. In addition, we observe complex mutation clusters where combinations of de novo SVs, nucleotide substitutions and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%). Genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs but not an elevated rate of genome rearrangement.

Genomics↗