Pleiotropy has long been thought to be a common phenomenon in the human genome; however, until recently appropriate data was unavailable to test this hypothesis. Prior studies focused on assessing the prevalence of pleiotropy in only small subsets of phenotypes (≤ 53 phenotypes), without a truly comprehensive assessment of pleiotropy in the human genome. In this study, we determined the prevalence of pleiotropy, using the entire GWAS catalog (1094 disease phenotypes, 14,459 genes), as well as investigate the relationship between the degree of pleiotropy and the average effect size for each associating gene. The number of associating phenotypes per gene ranged from 1 to 53, with 44% of genes reported in the GWAS catalog associating with more than one phenotype. The proportion of genes shown to be pleiotropic has continued to increase as more studies are added to the catalog. We also found the degree of pleiotropy scales positively with a gene's average effect size (r = 0.04, p value = 0.0003) and negatively with the variance of effect sizes in genes with a given number of associating phenotypes (r = − 0.590, p value = 0.0019). Based on this and prior work, it is becoming evident that pleiotropy is a common, if not ubiquitous, phenomenon. These results have implications in understanding disease etiologies, potentially common biology underlying even disparate diseases, and in elucidating the genotype-phenotype map.

Objective-To determine whether maternal/fetal SNPs in candidate genes are associated with preterm prelabor rupture of membranes (pPROM).Study Design-A case-control study was conducted in patients with pPROM (225 mothers and 155 fetuses) and 599 mothers and 628 fetuses with a normal pregnancy; 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; FDR was used to correct for multiple testing (q*=0.15)].Results-1) A SNP in TIMP2 in mothers was significantly associated with pPROM(OR=2.12 95% CI [1.47-3.07], p = 0.000068), and this association remained significant after correction for multiple comparisons; 2) Haplotypes for COL4A3 in the mother were associated with pPROM (global p = 0.003); 3) Multilocus analysis identified a three locus model, which included maternal SNPs in COL1A2, DEFA5, and EDN1.Conclusion-DNA variants in a maternal gene involved in extracellular matrix metabolism doubled the risk of pPROM.

Objective To determine whether maternal/fetal SNPs in candidate genes are associated with spontaneous preterm labor/delivery. Study Design A genetic association study was conducted in 223 mothers and 179 fetuses [preterm labor with intact membranes who delivered <37 weeks (PTB)], and 599 mothers and 628 fetuses (normal pregnancy): 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; FDR was used to correct for multiple testing (q*=0.15)]. Results 1) The strongest single locus associations with PTB were IL6R (fetus: p=0.000148) and TIMP2 (mother: p=0.000197), remaining significant after correction for multiple comparisons; 2) Global haplotype analysis indicated an association between a fetal DNA variant in IGF2 and maternal COL4A3 (global p=0.004 and 0.007, respectively). Conclusion A SNP involved in controlling fetal inflammation (IL6R) and DNA variants in maternal genes encoding for proteins involved in extracellular matrix biology approximately doubled the risk of PTB.

Autism is characterized as one of the Pervasive Developmental Disorders (PDDs), a spectrum of often severe behavioral and cognitive disturbances of early development. The high heritability of autism has driven multiple efforts to identify genetic variation that increases autism susceptibility. Numerous studies have suggested that variation in peripheral and central metabolism of serotonin (5-HT) may play a role in the pathophysiology of autism. We screened 403 autism families for 45 SNPs in 10 serotonin pathway candidate genes. Although genome-wide linkage scans in autism have provided support for linkage to various loci located within the serotonin pathway, our study does not provide strong evidence for linkage to any specific gene within the pathway. The most significant association (p=0.0002; p=0.02 after correcting for multiple comparisons) was found at rs1150220 (HTR3A) located on Chromosome 11 (~113 Mb). To test specifically for multilocus effects, Multifactor Dimensionality Reduction (MDR) was employed, and a significant 2-way interaction (p-value = 0.01) was found between rs10830962, near MTNR1B (Chromosome11; 92,338,075 bp) and rs1007631, near SLC7A5 (Chromosome16; 86,413,596 bp). These data suggest that variation within genes on the serotonin pathway, particularly HTR3A, may have modest effects on autism risk.