Genetics and Age Related

Hearing Impairment

Alexandra Costlow

Epidemiology Karlsson, Harris, & Svartengren (1997).

Swedish study comparing age related hearing impairment (ARHI) in monozygotic (MZ) and dizygotic (DZ) twins.

557 pairs: 250 (MZ), 307 (DZ).

Ages 36 – 80 years.

All males; audiologically representative sample.

Mean hearing thresholds at 3000, 4000, 6000, and 8000 Hz in both ears – used the better hearing ear.

Also used a questionnaire that inquired about pre- and perinatal health, noise and solvent exposure, etc …

Exclusion: Noise, ear disease, family history of specific hearing disorders.

Karlsson et al. (1997)

MZ twins share 100% of the same genetic material so genetics contribute to only shared similarities.

DZ twins share approximately half of the same genetic material and genetics contribute to both similarities and differences.

Additive Genetic Effects: The summative effect of alleles at 2+ loci is equal to the sum of their individual effects.

Nonadditive Genetic Effects: Intralocus dominance or interlocus epistasis.

Environmental influences are considered shared or individual.

Karlsson et al. (1997)

Hearing sensitivity decreased with age in this cross-sectional study.

Variation in hearing sensitivity increased with age.

MZ: Intraclass correlation decreased from 0.72 to 0.52.

DZ: Intraclass correlation increased from 0.13 to 0.28.

What inferences can we make?

Karlsson et al. (1997)

Results indicate that both genetic and environmental factors influence ARHI, but that environmental factors play a larger role with increased age.

Environmental influences of the nonshared type have a greater effect on ARHI.

Variation artificially decreases for participants older than 65 years of age due to the limits of the audiometer intensity.

Spouse Versus Sibling

Gates, Couropimtree, & Myers (1999).

Framingham Heart Study (and Framingham Offspring Study).

Another nature versus nurture study.

Hypothesis I: Correlation of hearing will be higher in related pairs (sibling) than in unrelated pairs (spousal) if genetic factors contribute.

Hypothesis II: With asymmetrical HL, genetic factors are implicated if familial aggregation of hearing thresholds occur in the BHE.

Gates et al. (1999) Framingham Cohort

Used low-, mid-, and high-frequency pure tone averages (PTAs).

Participants (several hundred, N depends on pair assignment/s) could belong to more than one pair.

Adjusted for age and for having a family member in the study No selection bias, which would likely cause an artificially greater effect rather than lesser effect.

Familial Aggregation of Hearing Thresholds: Correlation is greatest for mother-daughter pairs, consistent with other studies that indicate heritability is stronger among women*.

Framingham Cohort

Sensory Presbycusis Phenotype: Participants with normal hearing or sensory presbycusis phenotype.

Strong familial aggregation of age-adjusted hearing sensitivity.

Greatest associations: Mother-daughter. Sister-sister. Brother-brother. For all 3 PTAs. Low-frequency PTA has the strongest correlation, especially for

sister-sister and mother-daughter pairs.

No association: Father-child. Suggests strong effect of environmental factors on fathers’

hearing loss.

Framingham Cohort

Strial Presbycusis Phenotype: Flat audiometric pattern and normal hearing participants.

Strong familial association: Sister-sister. Mother-daughter. Strial presbycusis tends to be more common in females and

these results suggest a genetic basis for female subjects.

Low familial association: Sister-brother.

No association: Father-son. Brother-brother. *Small number of each of these pairs prevents a significance

estimate.

Framingham Cohort

Sensory presbycusis: 35 – 55% of the variance is attributable to genetic influence.

Strial presbycusis: 25 – 42% of the variance is attributatble to genetic influence.

Variance is higher for the low-frequency PTA (heritability = .50 - .53) than for the sensory phenotype.

Overall, hearing is more similar among related participants Suggests a genetic influence.

Low-frequency PTA has the strongest correlation, especially for sister-sister and mother-daughter pairs.

Suggests that both genetics and environment affect ARHI. Heritability ranged from 0.26 – 0.35.

Two Kinds of Epidemiologic Studies

Linkage: Examine families to identify the regions that may contain a candidate gene. The first step in a linkage study is to determine a population that displays a trait that you want to investigate.

Association: One step beyond linkage studies are association studies, which search for genetic (DNA) variants that are associated with ARHI within an unrelated sample. Often times functional candidate genes, such as those known to cause other types of hearing loss, are targeted as a starting point to search for DNA variants.

Genomewide Linkage Analysis to Presbycusis

The Framingham Heart Study.

DeStefano, Gates, Heard-Costa, Myers, & Baldwin (2003).

Objective: “To identify chromosomal regions that show evidence of linkage to age-associated hearing impairment in humans” (p. 285).

Heritability of mid- and low-frequencies is 0.38 and 0.31, respectively.

Linkage Analysis identified 3 regions of interest: 11p, 11q, 14q*.

DeStefano et al. (2003)

DeStefano, et al. (2003)

DeStefano, et al. (2003)

Ch. 10q peak of the multipoint analysis coincides with myo7a gene, which causes Usher Syndrome Type 1B and non-syndromic recessive deafness DFNB2. May suggest that this is an allelic variation of the same

gene that causes Usher Syndrome Type 1B that presents as a less severe hearing loss phenotype.

Ch. 11p overlaps with Usher Syndrome 1C locus.

Ch. 11q overlaps with DFNB20, which was identified in a consanguineous family from Pakistan.

Ch. 14q overlaps with Usher Syndrome 1a locus.

Ch. 10q and 18q do not overlap with known loci for deafness.

Murine ModelLandmark Study

Erway, Willot, Archer, & Harrison (1993).

5 inbred strains: CBA/HT-6J aka CH DBA/2J aka D2 C57BL.6J aka B6 BALB/cBYJ aka BY WB/ReJ aka WB

10 F1 hybrids.

Obtained click and tone pip thresholds (4, 8, 16, 24, 32k Hz) at 12, 16, and 23 months of age.

Erway et al. (1993)

Erway et al. (1993)

Erway et al. (1993)

1. The gene/s for ARHI are recessive. All CH hybrids have superior hearing than the

inbred strains (D2, B6, BY, WB). The dominant CH allele masks the recessive allele from the inbred strains.

2. Hybrid vigor is apparent in the F1 CH hybrids. This is the first study to demonstrate this in old

mice suggesting that this mechanism may be effective throughout a lifespan of 23 months.

Erway et al. (1993)

3. Three different genes cause ARHI in B6, BY, and WB strains. All 3 hybrids produce offspring with better hearing

than either of the parental inbred strains. All 3 parental inbred strains exhibit severe ARHI. Offspring are “normal.” Indicates that the parents possess different genes

that contribute to the same trait, aka complementation.

Each parent contributes a dominant allele at one locus and a recessive allele at the other locus.

Erway et al. (1993)

4. Because the 3 putative genes for hearing loss are recessive, a strain must be homozygous recessive for an allele to be expressed.

5. Possible imprinting of parental origin with age, which occurs when certain genes are expressed in a parent-of-origin manner. The imprinted gene is silenced. This is not Mendelian inheritance.

Aha! Ahl.

Johhnson, Erway, Cook, Willott, & Zheng, (1997).

C57BL/6L mice were backcrossed to CAST/Ei mice.

C57 mice are affected by the Ahl gene by 12 months of age.

CAST mice retain good hearing sensitivity until at least 2 years of age.

F1 hybrids were backcrossed to Cast/Ei inbreds to allow for genotypic segregation in the congenic strain.

Obtained click and tone pip (8, 16, 32k Hz) ABR thresholds at 10, 12, and 18 months of age.

Ahl is isolated to Chromosome 10 and codes for Cadherin23.

Cadherin23

Protein.

Cell adhesion.

Short version in the retina, long version in the inner ear.

Interacts with other proteins in the cell membrane to promote adhesion.

May shape inner ear hair bundles by cross-linking stereocilia.

Implicated in DFNB12 and Usher Syndrome 1D.

Mcb.harvard.edu

Genetics Home ReferenceGhr.nlm.nih.gov

Cadherin23

Genetics Home ReferenceGhr.nlm.nih.gov

Johnson et al. (1997)

mtDNA

Fischel-Ghodsian, et al. (1997).

5 participants with presbycusis.

3 control participants without prebycusis.

mtDNA mutations increase with age.

mtDNA is inherited maternally.

mtDNA mutations accrue faster than DNA mutations, and in inverse proportion to the length of the molecule.

Phenotype depends on the severity of the mutation (Seidman, et al., 1996).

Mayo.edu

mtDNA

Karyotype

Ghr.nhl.nih.gov

Other Genes

Modifier of deaf waddler (mdfw) locus (Zheng & Johnson, 2001). Mdfw on Ch. 10 maps to the same loci as Ahl. Mdfw acts epistatically with dfw on Ch. 6. Suggests that mdfw and Ahl are manifestations of the same

gene.

KCNQ4 (Van Eyken, 2006). Potassium voltage-gated channel. Ch. 4. Responsible for ADNSD DFNA2.

GRHL2 (Van Laer, et al. 2007). Protein acts as a homo- or heterodimer. Grainy head like 2. Ch. 8q22.3. Responsible for ADNSN DFNA28.

Other Genes

Hfhl1 and Hfhl3.

Chromosomes 7 and 9, respectively.

Discovered through linkage analysis last week.

Keller, J., & Noben-Trauth, K. (2012 in production).

DPOAEs in Swiss NIH mice indicated HFSNHL above 24 and 35kHz, respectively.

Confirmed previous research that employed ABR thresholds.

Implications

Counseling regarding disease progression.

Counseling regarding heritability.

Counseling regarding prevalence.

Isolating homologous genes in humans.

Pharmacologic therapy.

Gene silencing.

References

Christensen, K., Frederiksen, H., & Hoffman, H. (2001). Genetic and environmental influences on self-reported reduced hearing in the old and the oldest old. Journal of the American Genetics Society, 49(11), 1512 – 1517.

Crawley, B.K., & Keithley, E.M. (2011). Effects of mitochondrial mutations on hearing and cochlear pathology with age. Hearing Research, 280, 201 – 208.

DeStefano, A., Gates, G., Heard-Costa, N., Myers, R., & Baldwin, C. (2003). Genomewide linkage analysis to presbycusis in the Framingham Heart Study. Archives of Otolaryngology, Head and Neck Surgery, 129, 285 – 289.

Erway, L.C., Willott, J.F., Archer, J.R., & Harrison, D.E. (1993). Genetics of age-related hearing loss in mice: I. Inbred and F1 hybrid strains. Hearing Research, 65(1 – 2), 125 – 132.

Fischel-Ghodsian, N., Bykhovskaya, Y., Taylor, K., Kahen, T., Cantor, R., Ehrenman, K., Smith, R., Keithley, E. (1997). Temporal bone analysis of patients with presbycusis reveals high frequency of mitochondrial mutations. Hearing Research, 110, 147 – 154.

Fransen, E., Lemkens, N., Van Laer, L., & Van Camp, G. (2003). Age-related hearing impairment (ARHI): Environmental risk factors and genetic prospects. Experimental Gerontology, 38, 353 – 359.

Gates, G.A., Cooper, J.C., Jr., Kannel, W.B., & Miller, N.J. (1990). Hearing in the elderly: The Framingham Cohort , 1983 – 1985. Part I. Basic audiometric test results. Ear & Hearing, 11(4), 247 – 256 

Gates, G.A., Couropmitree, N.N., & Myers, R.H. (1999). Genetic associations in age-related hearing thresholds. Archives of Otolaryngology, Head and Neck Surgery, 125, 654 – 659.

Johnson, K.R., Erway, L.C., Cook, S.A., Willott, J.F., & Zheng, Q.Y. (1997). A major gene affecting age-related hearing loss in C57BL/6J mice. Hearing Research, 114(1 – 2), 83 – 92.

Johnson, K.R., Longo-Guess, C., Gagnon, L.H., Yu, H., & Zheng, Q.Y. (2008). A locus on distal chromosome 11 (ahl8) and its interaction with Cdh23 underlie the early, age-related hearing loss of DBA/2J mice. Genomics, 92, 219 – 225.

Johnson, K.R., Zheng, Q.Y., & Erway, L.C. (2000). A major gene affecting age-related hearing loss is common to at least ten inbred strains of mice. Genomics, 70(2), 171 – 180.

References

Karlsson, K., Harris, J., & Svartengren, M. (1997). Description and primary results from an audiometric study of male twins. Ear and Hearing, 18(2), 114 – 120.

Keller, J., & Noben-Trauth, K. (In production). Genome-wide linkage analyses identify Hfhl1 and Hfhl3 with frequency-specific effects on the hearing spectrum of NIH Swiss mice. BMC Genetics, 13(32).

Moscicki, E., Elkins, E., Baum, H., & McNamara, P. (1985). Hearing loss in the elderly: An epidemiologic study of the Framingham Heart Study Cohort. Ear & Hearing, 6(4), 184 – 190.

Noben-Trauth, K., Zheng, Q.Y., & Johnson, K.R. (2003) Association of cadherin 23 with polygenic inheritance and genetic modification of sensorineural hearing loss. Nature Genetics, 35, 21 – 23.

Raynor, L., Pankow, J., Miller, M., Huang, G., Dalton, D., Klein, R., Klein, B., & Cruickshanks, K. (2009). Familial aggregation of age-related hearing loss in an epidemiological study of older adults. Journal of the American Academy of Audiology, 18, 114-118.

Seidman, M., Bai, U., Khan, M., Murphy, M., Quirk, W., Castora, F., & Hinojosa, R. (1996). Association of mitochondrial DNA deletions and cochlear pathology: A molecular biologic tool. Laryngoscope, 106, 777 – 783.

Someya, S., Xu, J., Kondo, K., Ding, D., Salvi, R., Yamasoba, T., Rabinovitch, P., Weindruch, R., Leeuwenburgh, C., Tanokura, M., & Prolla, T. (2009). Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis. Proceedings of the National Academy of Sciences, 106(46), 19432 – 19437.

Van Eyken, E., Van Laer, L., Fransen, E., Topsakal, V., Lemkens, N., Laureys, W., Nelissen, N., Vandevelde, A., Wienker, T., Van De Heyning, P., & Van Camp, G. (2006). KCNQ4: A gene for age-related hearing impairment? Human Mutation, 27, 1007 – 1016.

Van Laer, E., et al. (2008). The grainyhead like 2 gene (GRHL2), alias TFCP2L3, is associated with age-related hearing impairment. Human Molecular Genetics, 17, 159 – 169.

 Yamasoba, T., Someya, S., Yamada, C., Weindruch, R., Prolla, T.A., & Tanokura, M. (2007). Role of mitochondrial dysfunction and mitochondrial DNA mutations in age-related hearing loss. Hearing Research, 226, 185 – 193.

Zheng, Q.Y., & Johnson, K.R. (2001). Hearing loss associated with the modifier of deaf waddler (mdfw) locus corresponds with age-related hearing loss in 12 inbred strains of mice. Hearing Research, 154, 45 – 53.