Whole-genome sequencing suggests mechanisms for 22q11.2 deletion-associated Parkinson's disease.

OBJECTIVES: To investigate disease risk mechanisms of early-onset Parkinson's disease (PD) associated with the recurrent 22q11.2 deletion, a genetic risk factor for early-onset PD. METHODS: In a proof-of-principle study, we used whole-genome sequencing (WGS) to investigate sequence variants in nine adults with 22q11.2DS, three with neuropathologically confirmed early-onset PD and six without PD. Adopting an approach used recently to study schizophrenia in 22q11.2DS, here we tested candidate gene-sets relevant to PD. RESULTS: No mutations common to the cases with PD were found in the intact 22q11.2 region. While all were negative for rare mutations in a gene-set comprising PD disease-causing and risk genes, another candidate gene-set of 1000 genes functionally relevant to PD presented a nominally significant (P = 0.03) enrichment of rare putatively damaging missense variants in the PD cases. Polygenic score results, based on common variants associated with PD risk, were non-significantly greater in those with PD. CONCLUSIONS: The results of this first-ever pilot study of WGS in PD suggest that the cumulative burden of genome-wide sequence variants may contribute to expression of early-onset PD in the presence of threshold-lowering dosage effects of a 22q11.2 deletion. We found no evidence that expression of PD in 22q11.2DS is mediated by a recessive locus on the intact 22q11.2 chromosome or mutations in known PD genes. These findings offer initial evidence of the potential effects of multiple within-individual rare variants on the expression of PD and the utility of next generation sequencing for studying the etiology of PD.

Genome-wide rare copy number variations contribute to genetic risk for transposition of the great arteries.

BACKGROUND: Transposition of the great arteries (TGA) is an uncommon but severe congenital heart malformation of unknown etiology. Rare copy number variations (CNVs) have been implicated in other, more common conotruncal heart defects like tetralogy of Fallot (TOF), but there are as yet no CNV studies dedicated to TGA. METHODS: Using high-resolution genome-wide microarrays and rigorous methods, we investigated CNVs in a group of prospectively recruited adults with TGA (n=101) from a single center. We compared rare CNV burden to well-matched cohorts of controls and TOF cases, adjudicating rarity using 10,113 independent population-based controls and excluding all subjects with 22q11.2 deletions. We identified candidate genes for TGA based on rare CNVs that overlapped the same gene in unrelated individuals, and pre-existing evidence suggesting a role in cardiac development. RESULTS: The TGA group was significantly enriched for large rare CNVs (2.3-fold increase, p=0.04) relative to controls, to a degree comparable with the TOF group. Extra-cardiac features were not reliable predictors of rare CNV burden. Smaller rare CNVs helped to narrow critical regions for conotruncal defects at chromosomes 10q26 and 13q13. Established and novel candidate susceptibility genes identified included ACKR3, IFT57, ITGB8, KL, NF1, NKX1-2, RERE, SLC8A1, SOX18, and ULK1. CONCLUSIONS: These data demonstrate a genome-wide role for rare CNVs in genetic risk for TGA. The findings provide further support for a genetically-related spectrum of congenital heart disease that includes TGA and TOF.

Fetal growth and gestational factors as predictors of schizophrenia in 22q11.2 deletion syndrome.

PURPOSE: Schizophrenia occurs in 20-25% of adults with 22q11.2 deletion syndrome (22q11.2DS). General population studies of schizophrenia report associations with perinatal complications, although effect sizes are generally low. We aimed to determine whether such factors are associated with expression of schizophrenia in individuals with 22q11.2DS. METHODS: We investigated the relationship of small for gestational age (SGA) birth weight (<3rd percentile for sex and gestational age) and prematurity (<37 weeks gestation) to expression of schizophrenia in a well-characterized cohort of 123 adults with 22q11.2DS. Outcome measures included adjusted odds ratios and positive and negative predictive values (PPV and NPV) for schizophrenia. RESULTS: SGA birth weight (OR = 3.52, 95% CI = 1.34-9.22) and prematurity (OR = 5.38, 95% CI = 1.63-17.75), but not maternal factors, were significant risk factors for schizophrenia in 22q11.2DS. Being born SGA or premature resulted in a PPV of 46% for schizophrenia; NPV in the absence of both features was 83%. Post hoc analyses suggested these perinatal complications were also associated with factors indicative of increased severity of schizophrenia. CONCLUSION: In 22q11.2DS, fetal growth and gestation may have a clinically significant impact on future risk for schizophrenia. These data advance our understanding of determinants of disease-specific expression in 22q11.2DS, with implications for other genomic disorders.Genet Med 18 4, 350-355.

Whole-Genome Sequencing Suggests Schizophrenia Risk Mechanisms in Humans with 22q11.2 Deletion Syndrome.

Chromosome 22q11.2 microdeletions impart a high but incomplete risk for schizophrenia. Possible mechanisms include genome-wide effects of DGCR8 haploinsufficiency. In a proof-of-principle study to assess the power of this model, we used high-quality, whole-genome sequencing of nine individuals with 22q11.2 deletions and extreme phenotypes (schizophrenia, or no psychotic disorder at age >50 years). The schizophrenia group had a greater burden of rare, damaging variants impacting protein-coding neurofunctional genes, including genes involved in neuron projection (nominal P = 0.02, joint burden of three variant types). Variants in the intact 22q11.2 region were not major contributors. Restricting to genes affected by a DGCR8 mechanism tended to amplify between-group differences. Damaging variants in highly conserved long intergenic noncoding RNA genes also were enriched in the schizophrenia group (nominal P = 0.04). The findings support the 22q11.2 deletion model as a threshold-lowering first hit for schizophrenia risk. If applied to a larger and thus better-powered cohort, this appears to be a promising approach to identify genome-wide rare variants in coding and noncoding sequence that perturb gene networks relevant to idiopathic schizophrenia. Similarly designed studies exploiting genetic models may prove useful to help delineate the genetic architecture of other complex phenotypes.

Reproductive Health Issues for Adults with a Common Genomic Disorder: 22q11.2 Deletion Syndrome.

22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans. Survival to reproductive age and beyond is now the norm. Several manifestations of this syndrome, such as congenital cardiac disease and neuropsychiatric disorders, may increase risk for adverse pregnancy outcomes in the general population. However, there are limited data on reproductive health in 22q11.2DS. We performed a retrospective chart review for 158 adults with 22q11.2DS (75 male, 83 female; mean age 34.3 years) and extracted key variables relevant to pregnancy and reproductive health. We present four illustrative cases as brief vignettes. There were 25 adults (21 > age 35 years; 21 female) with a history of one or more pregnancies. Outcomes for women with 22q11.2DS, compared with expectations for the general population, showed a significantly elevated prevalence of small for gestational age liveborn offspring (p < 0.001), associated mainly with infants with 22q11.2DS. Stillbirths also showed elevated prevalence (p < 0.05). Not all observed adverse events appeared to be attributable to transmission of the 22q11.2 deletion. Recurring issues relevant to reproductive health in 22q11.2DS included the potential impact of maternal morbidities, inadequate social support, unsafe sexual practices, and delayed diagnosis of 22q11.2DS and/or lack of genetic counseling. These preliminary results emphasize the importance of early diagnosis and long term follow-up that could help facilitate genetic counseling for men and women with 22q11.2DS. We propose initial recommendations for pre-conception management, educational strategies, prenatal planning, and preparation for possible high-risk pregnancy and/or delivery.

MicroRNA Dysregulation, Gene Networks, and Risk for Schizophrenia in 22q11.2 Deletion Syndrome.

The role of microRNAs (miRNAs) in the etiology of schizophrenia is increasingly recognized. Microdeletions at chromosome 22q11.2 are recurrent structural variants that impart a high risk for schizophrenia and are found in up to 1% of all patients with schizophrenia. The 22q11.2 deletion region overlaps gene DGCR8, encoding a subunit of the miRNA microprocessor complex. We identified miRNAs overlapped by the 22q11.2 microdeletion and for the first time investigated their predicted target genes, and those implicated by DGCR8, to identify targets that may be involved in the risk for schizophrenia. The 22q11.2 region encompasses seven validated or putative miRNA genes. Employing two standard prediction tools, we generated sets of predicted target genes. Functional enrichment profiles of the 22q11.2 region miRNA target genes suggested a role in neuronal processes and broader developmental pathways. We then constructed a protein interaction network of schizophrenia candidate genes and interaction partners relevant to brain function, independent of the 22q11.2 region miRNA mechanisms. We found that the predicted gene targets of the 22q11.2 deletion miRNAs, and targets of the genome-wide miRNAs predicted to be dysregulated by DGCR8 hemizygosity, were significantly represented in this schizophrenia network. The findings provide new insights into the pathway from 22q11.2 deletion to expression of schizophrenia, and suggest that hemizygosity of the 22q11.2 region may have downstream effects implicating genes elsewhere in the genome that are relevant to the general schizophrenia population. These data also provide further support for the notion that robust genetic findings in schizophrenia may converge on a reasonable number of final pathways.