Screening of genes interacting with high myopia and neuropsychiatric disorders

Abstract

Clinical studies have demonstrated an association between high myopia (HM) and neuropsychiatric disorders; however, the underlying mechanism of the association is not clear. We used whole exome sequencing (WES) in combination with the Genetic Variants Classification Criteria and Guidelines published by the American College of Medical Genetics (ACMG) and bioinformatics analysis to clarify the interrelationship between candidate genes. Causative genes for ocular diseases (45.38%) followed by neuropsychiatric disorders (22.69%) accounted for the highest proportion of genes that exhibited high pathogenicity in HM patients were found. Four pathogenic gene mutations were identified according to ACMG guidelines: c.164_165insACAGCA and c.C1760T in POLG, c.G1291A in COL5A1, and c.G10242T in ZNF469. Three causative genes for neuropsychiatric diseases, PTPRN2, PCDH15 and CDH23, were found to fall at the HM locus. The above results suggest that these genes may interact in high myopia and neuropsychiatric diseases.

Figure 1

Overview of the screening process. A range of strategies were applied to filter the causative genes for high myopia and neuropsychiatric disorders in 83 sporadic patients. Mutation frequency in populations, Mutation pathogenicity prediction, and ACMG are combined to narrow down the candidate genes and mutations.

Figure 2

Distribution of strongly pathogenic genes corresponding to various diseases in patients with high myopia. Genes of neuropsychiatric disorders for 22.69%; genes of ocular disease for 45.38%; genes of skeletal-related disease for 5.04%; genes of hormone-related disease for 0.84%; genes of blood disease for 1.68%; genes of mitochondrial disease for 0.84%; genes of deafness for 2.52%; genes of kidney disease for3.36%; genes of others for17.65%.

Figure 3

Distribution of disease-related genes among novel mutations. 18 causative genes were included in novel mutations for eye diseases (40%), 14 causative genes for brain diseases (31%), 4 causative genes for skeletal-related disorders (9%), 2 causative genes for deafness (4%), and only 1 causative gene for both hormone-related genes and blood disease (2%).

Figure 4

Distribution of disease-related genes among rare mutations. The proportion of rare mutations in various disease-related genes was 36 (49%) for eye disease genes, 13 (18%) for brain disease genes, 3 (4%) for kidney disease genes, 2 (3%) for bone-related genes, and 1 (1%) for both deafness and blood-related genes.

Figure 5

Protein interactions of neuropsychiatric and ocular diseases. One of the gene clusters was SOX5, COL9A1, COL4A5, COL5A1, LTBP2, CYP1B1, TGFBI, ZNF469, MYOF, and SLC4A11, with direct interactions between COL9A1, COL4A5, and COL5A1. The other gene cluster was PLCH, INPP5E, ARL13B, NPHP3, BBS2, BBS1, BBS9, NPHP1, CEP78, PLK4, and C5orf42, with the strongest interactions between ARL13B, NPHP3, BBS2, BBS1, and BBS9.

Figure 6

The pathogenicity heatmap of mutations. Different colors represent different degrees of pathogenicity; the darker the color, the greater is the pathogenicity.

Figure 7

Venn diagrams of genes involved in eye and neuropsychiatric diseases. 15 genes were found to be associated with both ocular and neuropsychiatric diseases.

Figure 8

Peak chromosome distribution map. Red indicates the specific location of the neuropsychiatric disease gene on the chromosome, and blue indicates the partial gene position where the neuropsychiatric disease gene and the HM locus overlap.