Rare Complement Factor H Variant Associated With Age-Related Macular Degeneration in the Amish

Hoffman, Joshua; Bailey, Jessica N. Cooke; D'Aoust, Laura; Cade, William H.; Ayala-Haedo, Juan; Fuzzell, Denise; Laux, Reneé; Adams, Larry D.; Reinhart-Mercer, Lori; Caywood, Laura J.; Whitehead-Gay, Patrice; Agarwal, Anita; Wang, Gaofeng; Scott, William K.; Pericak‐Vance, Margaret A.; Haines, Jonathan L.

doi:10.1167/iovs.13-13684

Cited by 49 publications

(74 citation statements)

References 33 publications

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“…None of the family members carried the rare AMD risk alleles at CFH R53C, CFH D90G, CFH P503A, or CFH R1210C [14][15][16]18 nor did they carry risk alleles for macular diseases in the BEST1, ABCA4, or other retinal degeneration-associated genes 25 . We measured serum FH levels in each family in order to assess the effects of the four CFH variants on secretion of the FH protein.…”

Section: Resultsmentioning

confidence: 96%

“…These two common variants explain 17% of AMD liability, but not everyone affected with AMD carries these variants 14 . Rare variants in CFH as well as other genes in the complement pathway have since been identified, and carry a higher risk of disease [14][15][16][17][18] . The CFH R53C variant, located in CCP1, decreases the ability of FH to perform decay accelerating activity 15 ; the CFH D90G variant, located in CCP2, was found to decrease cofactor-mediated inactivation 15 ; and the CFH R1210C variant, located in CCP20, shows defective binding of FH to C3d, C3b, heparin/glycosaminoglycans, and endothelial cells (Table 3) 14,30-33 .…”

Section: Discussionmentioning

confidence: 99%

“…Another rare variant was found to segregate with AMD in an Amish family, but no functional work was done to determine the effect of the mutation on FH protein. It is located in a CCP whose function is currently unknown 16 . Other variants in CFH were associated with basal laminar drusen 34,35 but no functional work was done to assess the effect of these variants.…”

Section: Discussionmentioning

confidence: 99%

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Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD

et al. 2016

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The genetic architecture of age-related macular degeneration (AMD) involves numerous genetic variants, both common and rare, in the coding region of complement factor H (CFH). While these variants explain high disease burden in some families, they fail to explain the pathology in all. We selected families whose AMD was unexplained by known variants and performed whole exome sequencing to probe for other rare, highly penetrant variants. We identified four rare loss-of-function variants in CFH associated with AMD. Missense variant CFH 1:196646753 (C192F) segregated perfectly within a family characterized by advanced AMD and drusen temporal to the macula. Two families, each comprising a pair of affected siblings with extensive extramacular drusen, carried essential splice site variant CFH 1:196648924 (IVS6+1G>A) or missense variant rs139360826 (R175P). In a fourth family, missense variant rs121913058 (R127H) was associated with AMD. Most carriers had early onset bilateral advanced AMD and extramacular drusen. Carriers tended to have low serum Factor H levels, especially carriers of the splice variant. One missense variant (R127H) has been previously shown not to be secreted. The two other missense variants were produced recombinantly: compared to wild type, one (R175P) had no functional activity and the other (C192F) had decreased secretion.Age-related macular degeneration (AMD), an irreversible degenerative disease, is the leading cause of blindness in adults over the age of 60. The disease affects the central region of the retina, resulting in progressive visual impairment and reduced quality of life. AMD is highly heritable and twin studies have shown that between 46% and 71% of phenotypic variance is explained by genetic factors 1,2 . Several environmental and genetic components contribute to its multifactorial etiology 2 . Early genome-wide scans for evidence of linkage in AMD families revealed several signals including one mapping to the long (q) arm of chromosome 1 [3][4][5] . Investigation of the genetic architecture of AMD subsequently evolved over the next 15 years on population, family, and individual levels. Genome-wide association studies (GWAS) and meta-GWAS efforts identified numerous genetic variants in over 20 different genes showing an association with AMD risk, including a common variant in the coding region of complement factor H (CFH) (RefSeq

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD

et al. 2016

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“…Studies in Finland (Lim et al 2014), Iceland (Gudbjartsson et al 2015), Greenland (Moltke et al 2014), Sardinia (Scott et al 2007), and among the Old Order Amish (Pollin et al 2008;Hoffman et al 2014) have all demonstrated how populations with a history of recent bottlenecks display large variations in allele frequencies.…”

Section: Characteristics Of Isolated Populationsmentioning

confidence: 99%

“…Thanks to next generation sequencing techniques, we are beginning to accumulate a large catalog of low-frequency and rare variants (1000Genomes Project Consortium 2015UK10K Consortium 2015; Genome of the Netherlands Consortium, 2014), a few of which have already been implicated in complex traits (Cohen et al 2005;Shuldiner et al 2009;Cruchaga et al 2014;Flannick et al 2014;Hoffman et al 2014;Lange et al 2014;Santos-Cortez et al 2015;Krumm et al 2015;Surakka et al 2015). However, current study designs are not optimal for detecting association with rare variants.…”

Section: Introductionmentioning

confidence: 99%

Finding Rare, Disease-Associated Variants in Isolated Groups: Potential Advantages of Mennonite Populations

Lopes¹,

Hou²,

Boldt³

et al. 2016

Human Biology

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Large-scale genotyping and next generation sequencing techniques have allowed great advances in the field of molecular genetics. Numerous common variants of low impact have been associated with many complex human traits and diseases, such as bipolar disorder and schizophrenia. Although they may exert a greater impact on risk, few rare disease variants have been found, owing to the greatly increased sample sizes that are typically necessary to demonstrate association with rarer variants. One alternative strategy is to study isolated populations, where historical bottlenecks reduce genetic diversity and some otherwise rare variants may drift to higher frequencies. Here we describe the Mennonite population settlements, considering their history of multiple bottlenecks followed by demographic expansion and a currently widespread geographical distribution. We argue that Mennonite populations are valuable partners for studies seeking to find genetic variants that exert a high impact on risk for a variety of common disorders, including mental illnesses.

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Rare Genetic Variants Associated With Development of Age-Related Macular Degeneration

et al. 2016

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IMPORTANCE Rare variants in the complement genes CFH, CFI, C9, and C3 have been found to be highly associated with age-related macular degeneration (AMD); however, the effect on clinical characteristics and familial segregation by these variants is lacking. OBJECTIVES To determine the contribution of rare CFH Arg1210Cys, CFI Gly119Arg, C9 Pro167Ser, and C3 Lys155Gln variants in the development of AMD in 22 multiplex families and to describe clinical differences in carriers vs noncarriers in these families and a large case-control cohort. DESIGN, SETTING, AND PARTICIPANTS This retrospective case-control study included 114 affected and 60 unaffected members of 22 multiplex families with AMD as well as 1589 unrelated patients with AMD and 1386 unrelated control individuals enrolled in the European Genetic Database (EUGENDA). Patients were recruited from March 29, 2006, to April 26, 2013, and data were collected from April 20, 2012, to May 7, 2014. All participants underwent an extensive ophthalmic examination and completed a questionnaire. Venous blood samples were obtained from all participants for genetic analysis, including whole-exome sequencing and measurements of complement activation. Data were analyzed from September 23, 2014, to November 4, 2015. MAIN OUTCOMES AND MEASURES Differences between carriers and noncarriers of rare variants in age at onset of symptoms, the family history of AMD, complement activation levels (C3d:C3 ratio), the presence of reticular pseudodrusen, and AMD phenotype. RESULTS Among the 114 affected and 60 unaffected members of 22 multiplex families with AMD and the 1598 unrelated patients with AMD and 1386 controls in the EUGENDA cohort who underwent analysis, the presence of the CFI Gly119Arg, C9 Pro167Ser, or C3 Lys155Gln variant was confirmed in 18 individuals in 5 families but did not completely segregate with the disease. In the case-control cohort, the 91 affected carriers of these variants were younger at symptom onset (mean [SD] age, 67.4 [8.5] vs 71.3 [8.9] years; P = .01) and more often reported a positive family history (35 of 79 [44.3%] vs 367 of 1201 [30.6%]; P = .008) compared with the 1498 noncarriers. Patients with advanced atrophic AMD carried these rare variants more frequently than patients with neovascular AMD (11 of 93 [11.8%] vs 40 of 835 [4.8%]; P = .04). CONCLUSIONS AND RELEVANCE Previously reported rare variants do not completely segregate within families with AMD. However, patients carrying these rare variants differ clinically from noncarriers by an earlier age at symptom onset, higher prevalence of a positive family history, and AMD phenotype. These results suggest that genetic tests for AMD might be designed to detect common and rare genetic variants, especially in families, because rare variants contribute to the age at onset and progression of the disease.

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Rare Complement Factor H Variant Associated With Age-Related Macular Degeneration in the Amish

Cited by 49 publications

References 33 publications

Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD

Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD

Finding Rare, Disease-Associated Variants in Isolated Groups: Potential Advantages of Mennonite Populations

Rare Genetic Variants Associated With Development of Age-Related Macular Degeneration

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