QTL replication and targeted association highlight the nerve growth factor gene for nonverbal communication deficits in autism spectrum disorders

Abstract

Autism Spectrum Disorder (ASD) has a heterogeneous etiology that is genetically complex. It is defined by deficits in communication and social skills and the presence of restricted and repetitive behaviors. Genetic analyses of heritable quantitative traits that correlate with ASD may reduce heterogeneity. With this in mind, deficits in nonverbal communication (NVC) were quantified based on items from the Autism Diagnostic Interview Revised. Our previous analysis of 228 families from the Autism Genetics Research Exchange (AGRE) repository reported 5 potential quantitative trait loci (QTL). Here we report an NVC QTL replication study in an independent sample of 213 AGRE families. One QTL was replicated (P < 0.0004). It was investigated using a targeted-association analysis of 476 haplotype blocks with 708 AGRE families using the Family Based Association Test (FBAT). Blocks in two QTL genes were associated with NVC with a P-value of 0.001. Three associated haplotype blocks were intronic to the Nerve Growth Factor (NGF) gene (P= 0.001, 0.001, 0.002), and one was intronic to KCND3 (P= 0.001). Individual haplotypes within the associated blocks drove the associations (0.003, 0.0004 and 0.0002) for NGF and 0.0001 for KCND3. Using the same methods, these genes were tested for association with NVC in an independent sample of 1517 families from an Autism Genome Project (AGP). NVC was associated with a haplotype in an adjacent NGF block (P= 0.0005) and one 46 kb away from the associated block in KCND3 (0.008). These analyses illustrate the value of QTL and targeted association studies for genetically complex disorders such as ASD. NGF is a promising risk gene for NVC deficits.

Evidence for differential alternative splicing in blood of young boys with autism spectrum disorders

“…Our novel pathway analysis supports previously published data on alterations in pathways in ASD, such as oxidative stress [61], mTOR [38], Natural Killer cells [59,60], NGF, and monocyte pathways [112], as well as activation of microglia (macrophages in the periphery) [22,109]. However, this is the first study to suggest DAS/DEU occurs in these pathways and thus confirmation is needed in a future independent cohort.…”

Gene hunting in autism spectrum disorder: on the path to precision medicine

“…However, no common variation has been identified or even reached the threshold of regional significance (correcting for multiple testing based on only those SNPs within the linkage region), perhaps with the exception of CNTNAP2 (contactin associated proteinlike 2) and NGF (nerve growth factor). 23,24 Additionally, no association signals have been found that can account for the linkage peaks in these regions, which suggests that even within segments shared by affected families, rare genetic variation is likely to be playing a significant part, consistent with the expectations of small individual-allele effect sizes from common variants. 25 …”

Harm avoidance involved in mediating the association between nerve growth factor (NGF) gene polymorphisms and antidepressant efficacy in patients with major depressive disorder

“…An exonic polymorphism, rs6330, was selected for comparison with previous psychotherapy studies (Lester et al, 2012;Hudson et al, 2013). We selected other six intronic SNPs: rs11102929 (Mercader et al, 2008), rs17033692 (Lu et al, 2013), rs7523654 (Gratacos et al, 2010), rs12760036 (Park et al, 2011), rs6678788 (Cui et al, 2011) in intron 1; and rs2254527 (Toma et al, 2013) in intron 2.…”