The quest for understanding the genetic contributions to IIH is critical to unravel the enigmatic nature of this disorder. Our study focused on a unique Middle Eastern village with a distinct prevalence of familial ties among the IIH patients, thus providing an opportunity to explore genetic associations in the context of a homogenous population with high consanguinity rates. By employing innovative methodologies, we aimed to shed light on potential genetic factors underlying this complex condition. Our findings indicated that within this distinctive population the presence of genetic loci was possibly associated with IIH. Traditional GWAS analyzes substantial sample sizes, which can be challenging in the context of rare conditions such as IIH. Nonetheless, we adopted a creative approach by analyzing long haplotypes rather than individual SNPs, capitalizing on the fact that the patients in our cohort were related, and therefore, our results were still significant.

This approach allowed us to uncover statistically significant associations despite our limited sample size, as reported in previous studies, which have successfully demonstrated genetic associations using small cohorts, i.e., the NORDIC IIHTT Study Group who identified three candidate regions on chromosomes 5, 13, and 14 with a relatively modest sized cohort of 95 patients and controls [10]. Intriguingly, we identified regions on chromosomes 16, 8, 1, and 6 that demonstrated potential associations with IIH susceptibility or protection (Table 1). Within chromosome 16, genes CA5A and BANP surfaced as potential contributors. CA5A encodes a carbonic anhydrase enzyme [23] linked to various metabolic processes, including obesity-related pathways [24,25,26,27,28,29]. As obesity is a known risk factor for IIH, the connection between CA5A and IIH could indicate novel mechanistic pathways underlying this correlation. Interestingly, acetazolamide, the first line of drugs in treating IIH, is a carbonic anhydrase inhibitor [30]. Similarly, BANP, a tumor suppressor and cell cycle regulator [31], might play a role in IIH etiology through interactions with p53 transcription.

On chromosome 8, while the precise gene could not be pinpointed due to the region's complexity, its association with IIH remains a promising avenue for future research. Protective effects were observed on chromosomes 1 and 6, where PBX1 and LMX1A are located. PBX1 is associated with osteogenesis and insulin gene regulation [32], whereas LMX1A is linked to dopamine-producing neuron development [33], potentially implicating dopaminergic pathways in IIH. Moreover, the identification of the ESR1 gene on chromosome 6, which is linked to estrogen-regulated processes [34], adds a layer of complexity to IIH's genetic landscape. As estrogen is known to influence various physiological functions, including adipose tissue distribution, our findings could suggest novel interactions between hormonal factors and IIH susceptibility.

Our study underscores the importance of tailoring genetic investigations to the unique characteristics of study populations. The distinctive nature of our cohort, with its high consanguinity and shared ancestry, facilitated the utilization of advanced analytical techniques, resulting in the identification of potentially relevant genetic associations. While the commonly used threshold for genome-wide association studies is 5 × 10−8–5 × 10−5, our unique cohort with familial connections led us to choose a more exploratory threshold of log10 (p value) of 2.0; hence, it is crucial to acknowledge the limitations of our study, primarily the modest sample size. However, we believe that our unique cohort with familial connections justifies our choice.

Our study is unique in that it focuses on a relatively rare disease, and a small, homogenous population with strong familial connections, therefore making it difficult to obtain a large sample size. Using a more exploratory threshold, we were able to identify candidate areas that may be associated with IIH in this population. In addition, we used a haplotype-based approach to estimate the associations with haplotypes instead of SNPs. Last, our pilot study aimed at identifying candidate areas that may be associated with IIH in a unique population. We acknowledge that our sample size is small and that our threshold is more exploratory than conventional thresholds. Nevertheless, we believe that our findings are promising and warrant further investigation in larger, well-phenotyped cohorts.

Several genes were identified as potential candidates associated with disease susceptibility; however, we acknowledge the speculative nature of these findings, particularly, considering our novel analytical approach. Our method introduces a new perspective, and while it holds promise, we recognize the need for caution in interpreting these preliminary associations. Despite this constraint, our approach offers a promising avenue for similar studies in other specialized cohorts with strong familial connections. As we move forward, it is imperative to expand the exploration of these loci through independent cohorts and functional studies. Future research should delve into the precise mechanisms by which these genes exert their effects in addition to investigating potential interactions with environmental factors.