Identification of quantitative trait loci for survival in the mutant dynactin p150Glued mouse model of motor neuron disease.

Amyotrophic lateral sclerosis (ALS) is the most common degenerative motor neuron disorder. Although most cases of ALS are sporadic, 5-10% of cases are familial, with mutations associated with over 40 genes. There is variation of ALS symptoms within families carrying the same mutation; the disease may develop in one sibling and not in another despite the presence of the mutation in both. Although the cause of this phenotypic variation is unknown, it is likely related to genetic modifiers of disease expression. The identification of ALS causing genes has led to the development of transgenic mouse models of motor neuron disease. Similar to families with familial ALS, there are background-dependent differences in disease phenotype in transgenic mouse models of ALS suggesting that, as in human ALS, differences in phenotype may be ascribed to genetic modifiers. These genetic modifiers may not cause ALS rather their expression either exacerbates or ameliorates the effect of the mutant ALS causing genes. We have reported that in both the G93A-hSOD1 and G59S-hDCTN1 mouse models, SJL mice demonstrated a more severe phenotype than C57BL6 mice. From reciprocal intercrosses between G93A-hSOD1 transgenic mice on SJL and C57BL6 strains, we identified a major quantitative trait locus (QTL) on mouse chromosome 17 that results in a significant shift in lifespan. In this study we generated reciprocal intercrosses between transgenic G59S-hDCTN1 mice on SJL and C57BL6 strains and identified survival QTLs on mouse chromosomes 17 and 18. The chromosome 17 survival QTL on G93A-hSOD1 and G59S-hDCTN1 mice partly overlap, suggesting that the genetic modifiers located in this region may be shared by these two ALS models despite the fact that motor neuron degeneration is caused by mutations in different proteins. The overlapping region contains eighty-seven genes with non-synonymous variations predicted to be deleterious and/or damaging. Two genes in this segment, NOTCH3 and Safb/SAFB1, have been associated with motor neuron disease. The identification of genetic modifiers of motor neuron disease, especially those modifiers that are shared by SOD1 and dynactin-1 transgenic mice, may result in the identification of novel targets for therapies that can alter the course of this devastating illness

Attitudes among Parents towards Return of Disease-Related Polygenic Risk Scores (PRS) for Their Children

The electronic MEdical Records and GEnomics (eMERGE) consortium will return risk reports pertaining to specific diseases, a key component of which will be polygenic risk scores (PRS), to 25,000 participants, including 5000 children. Understanding comprehension and the perceived value of these PRS-based reports among parents will be critical for effective return of results in children. To address this issue, we conducted semi-structured interviews with 40 African American and Hispanic parents at The Children’s Hospital of Philadelphia and Boston Children’s Hospital. Each participant received a hypothetical risk report identifying their child as high risk for either type 2 diabetes or asthma. Participants were assessed on their comprehension of absolute versus relative risk framing, likelihood of following risk-reduction recommendations, perceived value of the information, psychosocial impact, education/support needed, and suggestions to improve the PRS-based report to make it more accessible. Results demonstrated high perceived value in receiving PRS-based reports but also draws attention to important shortfalls in comprehension due to factors including the health of the child, family history, and how the risk was framed. This study provides an insight into implementing the return of genomic risk scores in a pediatric setting

One-dimensional scans for the survival phenotype with pval less than or equal to 0.63.

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Data dynactin F2 mice phenotype and genotype.

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Single nucleotide polymorphisms across the mouse genome used to differentiate C57BL/6J from SJL/J mice.

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Protein coding genes in the Chr17 QTL of G59S-hDCTN1 mice demonstrating non-synonymous variations deemed to be deleterious and/or damaging.

Protein coding genes in the Chr17 QTL of G59S-hDCTN1 mice demonstrating non-synonymous variations deemed to be deleterious and/or damaging.</p

Effect plot of genotype on health sacrifice at the chromosome 6 QTL.

Effect of genotype at chromosome 6, 33.5 cM on health sacrifice. The health sacrifice in days is plotted as the mean + SE. The genotypes are BB for homozygous B6, SS for homozygous SJL and BS for heterozygous B6/SJL. (TIF)</p

Effect of the paternal grandmother of the F2 cross on life span of G59S-hDCTN1 mice.

Effect of the paternal grandmother of the F2 cross on life span of G59S-hDCTN1 mice.</p

Survival curves for SOD1 and dynactin-1 transgenic mice.

Survival curves for transgenic C57BL6/J, SJL/J mice and their F2 cross with [A] the G93A human SOD1 transgene or [B] the G59S human dynactin-1 transgene.</p

Multiple regression model for the survival phenotype in G59S-hDCTN1 mice.

Multiple regression model for the survival phenotype in G59S-hDCTN1 mice.</p