Genome Sequencing & Tinnitus — Identifying Genetic Traits/Variations

One interesting aspect to all of this which I haven't seen discussed that much, is we now have the ability (and have had for quite some time) to have our genome sequenced, and then we can take that raw data and plug it into a tool like Promethease, which will look at genes you have which are noted in academic research, and in doing so, likely highlight traits that may make you more susceptible to developing conditions like tinnitus, like glutamate metabolism etc...

I am in the process of retrieving my raw data now, but curious if anyone else has done this. I used 23andMe for the sequencing and then will plug that data into secondary tools as needed.

Aspirationally, it would be cool if we could identify common genetic traits/variations amongst our community of afflicted, though that is just an idea.

 

I think this is interesting but does 23andMe really cover the full genome? I thought they only covered a part of it.

Hasn't @FGG done this 23andMe as well?

 

I believe they do genotyping and not sequencing. @Mods not sure if I can change the title to replace "sequencing" with "genotyping" for accuracy.

Per 23andMe:
Genotyping is the process of determining which genetic variants an individual possesses. Genotyping can be performed through a variety of different methods, depending on the variants of interest and the resources available. For looking at many different variants at once, especially common variants, genotyping chips are an efficient and accurate method. They do, however, require prior identification of the variants of interest.

 

23andMe retrieves a lot more than they report to you (which is next to nothing and only your genotype). But you can sign up for Promethease and give them permission to upload your genome from 23andMe and then you get a huge amount of info.

 

Alright, well I went through all of Promethease and there was nothing related to hearing, glutamate, or anything I could use for tinnitus, so this idea was short-lived.

 

Did you try searching for individual genes? Not just scrolling through the first page.

 

@FGG

I went through all of the genes highlighted for 4x, 2x trait probability etc... after that I tried a key word search on hearing, ear, auditory, glutamate, and a few other things.

Since I can’t find anything “top-down”, the other way is if I ever come across a specific gene I can search the record “bottom-up” for that specific element, but right now nothing sticks out. I will take another scroll through.

Right now takeaways are: high baldness probability (though has not manifested yet), elevated risk of certain cancers, slow metabolism, light sleeper, should be very muscley and tall, and reduced risk of Alzheimer’s and dementia : )

 

Right, you need to go bottom up. I didn't realize you already noticed that. The only way to do this is with the individual gene search feature. You can look at GABA genes etc but you have to first research which genes affect the receptors.

It doesn't tell you how to interpret these alleles but it tells you your genotype. But that's what I meant by having to compare with others. You'd basically have to do your own research by trying to see if any commonalities show up.

 

Ah okay, that makes perfect sense. Now we're getting into real researcher territory and away from my hobbyist abilities. I am smart enough to recognize that undertaking an analysis like this would be good idea, but not smart enough necessarily to do it. Did I mention in my past life I was a management consultant?

 

Novel Risk Loci in Tinnitus and Causal Inference With Neuropsychiatric Disorders Among Adults of European Ancestry

Key Points

Question What is the genetic architecture of tinnitus and its association with neuropsychiatric disorders?

Findings This genome-wide association study in 172 995 European adults from the UK Biobank identified 6 significant loci and 27 genes, with replication in 260 832 adults from the Million Veteran Program for 3 of 6 loci and 8 of 27 genes. Genetic correlations were identified between tinnitus and hearing loss, insomnia, and neuropsychiatric disorders, and evidence of relationships based on mendelian randomization was inferred for major depressive disorder, years of schooling, and hearing loss.

Meaning Characterization of the genetic architecture of tinnitus and identification of specific risk genes is critical for targeted clinical research into this pervasive disorder.

Abstract
Importance Tinnitus affects at least 16 million US adults, but its pathophysiology is complicated, and treatment options remain limited. A heritable component has been identified in family and twin studies; however, no large-scale genome-wide association studies (GWAS) have been accomplished.

Objective To identify genetic risk loci associated with tinnitus, determine genetic correlations, and infer possible relationships of tinnitus with hearing loss and neuropsychiatric disorders and traits.

Design, Setting, and Participants A GWAS of self-reported tinnitus was performed in the UK Biobank (UKB) cohort using a linear mixed-model method implemented in BOLT-LMM (linear mixed model). Replication of significant findings was sought in the nonoverlapping US Million Veteran Program (MVP) cohort. A total of 172 995 UKB (discovery) and 260 832 MVP (replication) participants of European ancestry with self-report regarding tinnitus and hearing loss underwent genomic analysis. Linkage-disequilibrium score regression and mendelian randomization were performed between tinnitus and hearing loss and neuropsychiatric disorders. Data from the UKB were acquired and analyzed from September 24, 2018, to December 13, 2019. Data acquisition for the MVP cohort was completed July 22, 2019. Data analysis for both cohorts was completed on February 11, 2020.

Main Outcomes and Measures Estimates of single nucleotide variation (SNV)–based heritability for tinnitus, identification of genetic risk loci and genes, functional mapping, and replication were performed. Genetic association and inferred causality of tinnitus compared with hearing loss and neuropsychiatric disorders and traits were analyzed.

Results Of 172 995 UKB participants (53.7% female; mean [SD], 58.0 [8.2] years), 155 395 unrelated participants underwent SNV-based heritability analyses across a range of tinnitus phenotype definitions that explained approximately 6% of the heritability. The GWAS based on the most heritable model in the full UKB cohort identified 6 genome-wide significant loci and 27 genes in gene-based analyses, with replication of 3 of 6 loci and 8 of 27 genes in 260 832 MVP cohort participants (92.8% men; mean [SD] age, 63.8 [13.2] years). Mendelian randomization indicated that major depressive disorder had a permissive effect (β = 0.133; P = .003) and years of education had a protective effect (β = −0.322, P = <.001) on tinnitus, whereas tinnitus and hearing loss inferred a bidirectional association (β = 0.072, P = .001 and β = 1.546, P = <.001, respectively).

Conclusions and Relevance This large GWAS characterizes the genetic architecture of tinnitus, demonstrating modest but significant heritability and a polygenic profile with multiple significant risk loci and genes. Genetic correlation and inferred causation between tinnitus and major depressive disorder, educational level, and hearing impairment were identified, consistent with clinical and neuroimaging evidence. These findings may guide gene-based diagnostic and therapeutic approaches to this pervasive disorder.

Source:
https://jamanetwork.com/journals/jamaotolaryngology/article-abstract/2770970

 

Article related to the one above.

A New Buzz for Tinnitus—It’s in the Genes!

“Does tinnitus run in your family?” Seldom is that question asked by clinicians to their patients with tinnitus, but why would they ask? Audiologists and ear, nose, and throat specialists see patients with tinnitus in association with either conductive or sensorineural hearing loss, which has led to the clinical dogma that tinnitus is secondary and by definition a symptom arising from the hearing disorder. However, tinnitus may occur in absence of any detectable auditory dysfunction, most particularly in young individuals, which raises the question on the origins of these more sporadic cases of phantom percept. In this issue of JAMA Otolaryngology–Head & Neck Surgery, Clifford et al present the first evidence in a genome-wide association study (GWAS) of 3 loci and 8 genes associated with tinnitus and replicated in 2 independent large cohorts of European ancestry: the UK Biobank and the Million Veterans Program. These findings go against the preconceived notion that tinnitus is purely a symptom and demonstrate that, at least in part, its neurological basis lies in the genes. A GWAS is the primary step in establishing the connection between genes and a trait by investigating the level of genetic variation between cases and controls. Thus, rather than looking at all the sequences from the entire genome, Clifford et al looked at specific sites across the whole genome, termed single-nucleotide variants (SNVs), where variations are expected to happen. A number of variants showed up consistently among individuals with tinnitus but not among those without tinnitus. Heritability of SNVs explained 6.3% of the variation; in other words, the identified SNVs explain nearly 6% of the trait. Including hearing difficulties as a covariate reduced tinnitus heritability by 18.8% to 35.6%, which reinforces the paradigm-shifting concept that not all tinnitus cases depend on hearing loss. With more than 1 gene being significantly associated with tinnitus, tinnitus can be defined as a polygenic disorder. Although these findings clearly demonstrate that tinnitus has a heritable component, they also indicate the importance of environmental factors in determining the full manifestation of tinnitus. Altogether, these features define tinnitus as a complex disorder, as opposed to rare mendelian disorders, wherein multiple genes and environmental factors interact together to generate a phenotype.

Source: https://jamanetwork.com/journals/jamaotolaryngology/article-abstract/2770968

 

Genome-wide association study identifies new loci associated with noise-induced tinnitus in Chinese populations

Genotyping of 711 noise-exposed male workers of Chinese Ancestry.